Unlocking cellular plasticity: Enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for Induced Pluripotent Stem Cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition (MET) during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.

Comprehensive observational study evaluating the enduring effectiveness of 4CMenB, the meningococcal B vaccine against gonococcal infections in the Northern Territory and South Australia, Australia: study protocol.

INTRODUCTION: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections. METHODS AND ANALYSES: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison. ETHICS AND DISSEMINATION: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

Enablers and barriers to primary health care access for Indigenous adolescents: a systematic review and meta-aggregation of studies across Australia, Canada, New Zealand, and USA.

BACKGROUND: Indigenous adolescents access primary health care services at lower rates, despite their greater health needs and experience of disadvantage. This systematic review identifies the enablers and barriers to primary health care access for Indigenous adolescents to inform service and policy improvements. METHODS: We systematically searched databases for publications reporting enablers or barriers to primary health care access for Indigenous adolescents from the perspective of adolescents, their parents and health care providers, and included studies focused on Indigenous adolescents aged 10-24 years from Australia, Canada, New Zealand, and United States of America. Results were analyzed against the WHO Global standards for quality health-care services for adolescents. An additional ninth standard was added which focused on cultural safety. RESULTS: A total of 41 studies were included. More barriers were identified than enablers, and against the WHO Global standards most enablers and barriers related to supply factors - providers' competencies, appropriate package of services, and cultural safety. Providers who built trust, respect, and relationships; appropriate package of service; and culturally safe environments and care were enablers to care reported by adolescents, and health care providers and parents. Embarrassment, shame, or fear; a lack of culturally appropriate services; and privacy and confidentiality were common barriers identified by both adolescent and health care providers and parents. Cultural safety was identified as a key issue among Indigenous adolescents. Enablers and barriers related to cultural safety included culturally appropriate services, culturally safe environment and care, traditional and cultural practices, cultural protocols, Indigenous health care providers, cultural training for health care providers, and colonization, intergenerational trauma, and racism. Nine recommendations were identified which aim to address the enablers and barriers associated with primary health care access for Indigenous adolescents. CONCLUSION: This review provides important evidence to inform how services, organizations and governments can create accessible primary health care services that specifically meet the needs of Indigenous adolescents. We identify nine recommendations for improving the accessibility of primary health care services for Indigenous adolescents.

Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS-CoV-2 infection in a mouse model with human angiotensin-converting enzyme 2 (ACE2) expression. Mice were infected with SARS-CoV-2 and treated with either vehicle or the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). At day 5 post-infection, SARS-CoV-2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6-8 post-infection. SARS-CoV-2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral-induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS-CoV-2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.

Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in Mouse.

Purpose: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. Methods: We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Contrary to prior publications, the KO was not neonatal lethal. Thus, we phenotyped the Adam19 KO. Results: KO mice had lower body weight and shorter tibial length than wild type (WT). Dual-energy X-ray Absorptiometry indicated lower soft weight, fat weight, and bone mineral content in KO mice. In lung function analyses using flexiVent, compared to WT, Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. Conclusion: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.

Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer.

The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNA polymerase II (RNAPII) transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed differentially open chromatin regions (DOCR). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic superenhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology. SIGNIFICANCE: Our study provides a strong basis for understanding the mechanisms by which proteasome inhibitors exert anticancer effects. We find open chromatin regions that change during proteasome inhibition, are typically accessible in non-basal breast cancers.

Genomic insights into the population history and adaptive traits of Latin American Criollo cattle.

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

Indigenous data governance approaches applied in research using routinely collected health data: a scoping review.

Globally, there is a growing acknowledgment of Indigenous Peoples' rights to control data related to their communities. This is seen in the development of Indigenous Data Governance standards. As health data collection increases, it's crucial to apply these standards in research involving Indigenous communities. Our study, therefore, aims to systematically review research using routinely collected health data of Indigenous Peoples, understanding the Indigenous Data Governance approaches and the associated advantages and challenges. We searched electronic databases for studies from 2013 to 2022, resulting in 85 selected articles. Of these, 65 (77%) involved Indigenous Peoples in the research, and 60 (71%) were authored by Indigenous individuals or organisations. While most studies (93%) provided ethical approval details, only 18 (21%) described Indigenous guiding principles, 35 (41%) reported on data sovereignty, and 28 (33%) addressed consent. This highlights the increasing focus on Indigenous Data Governance in utilising health data. Leveraging existing data sources in line with Indigenous data governance principles is vital for better understanding Indigenous health outcomes.

Preconception Health of Indigenous Peoples in Australia, Canada, New Zealand, and the United States: A Scoping Review.

BACKGROUND: There is increasing recognition of the importance of the preconception period for addressing reproductive and intergenerational health inequities and supporting improved maternal and child health outcomes. This study aimed to understand the extent and type of evidence that exists in relation to preconception health for Indigenous peoples living in high-income countries with similar experiences of colonisation, namely, Australia, New Zealand, Canada, and the United States. METHODS: This review was conducted as per the JBI methodology and PRISMA Extension for Scoping Reviews. A comprehensive search of PubMed, CINAHL [EBSCO], Ovid Embase, Scopus, and the Wiley Cochrane Library was conducted using keywords and index terms. We included research in English published between January 2010 and June 2023 on quantitative and qualitative primary studies. Data were extracted using a standardised tool, and the analysis included quantitative descriptions and qualitative content analysis. RESULTS: We identified 360 potential studies and included 57 articles in the review. Most studies were from the United States (n = 36, 63.2%) and Australia (n = 13, 22.8%), and they commonly reported associations between preconception health risk factors and maternal or child health outcomes (n = 27, 48.2%) or described the development, implementation, or evaluation of preconception health interventions (n = 26, 46.4%). Common preconception health areas were pre-pregnancy body mass index or weight (n = 34), alcohol (n = 16), diet (n = 14), physical activity (n = 12), and diabetes (n = 11). Most studies focused exclusively on women (n = 46, 80.7%), and very few included men (n = 3, 5.3%). The study populations were mostly urban and rural (n = 25, 43.9%) or rural only (n = 14, 24.6%); however, the geographical remoteness was often unclear (n = 14, 24.6%). CONCLUSIONS: While there was some research relating to the preconception health of Indigenous peoples, this review identified considerable research gaps. There is a need for dedicated research into preconception health risk factors and reproductive health outcomes, attitudes and awareness of preconception health, and preconception health interventions for Indigenous peoples.

BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates.

Cell fate decisions are achieved with gene expression changes driven by lineage-specific transcription factors (TFs). These TFs depend on chromatin remodelers including the Brahma-related gene 1 (BRG1)-associated factor (BAF) complex to activate target genes. BAF complex subunits are essential for development and frequently mutated in cancer. Thus, interrogating how BAF complexes contribute to cell fate decisions is critical for human health. We examined the requirement for the catalytic BAF subunit BRG1 in neural progenitor cell (NPC) specification from human embryonic stem cells. During the earliest stages of differentiation, BRG1 was required to establish chromatin accessibility at neuroectoderm-specific enhancers. Depletion of BRG1 dorsalized NPCs and promoted precocious neural crest specification and enhanced neuronal differentiation. These findings demonstrate that BRG1 mediates NPC specification by ensuring proper expression of lineage-specific TFs and appropriate activation of their transcriptional programs.

Patient and healthcare provider perceptions of acceptability of fingerstick point-of-care hepatitis C testing at Aboriginal Community Controlled Health Services in Australia.

BACKGROUND: Hepatitis C (HCV) is highly prevalent in First Nations communities globally. Barriers in the uptake of testing and treatment create challenges to realise elimination of HCV in these communities. In efforts to reduce barriers to testing and treatment, the SCALE-C study implemented an HCV test-and-treat intervention integrating point-of-care HCV testing and FibroScan®. SCALE-C was carried out at four Aboriginal Community Controlled Health Services (ACCHS; renowned for providing culturally safe care) in four regional towns in Australia. This qualitative analysis sought to understand healthcare provider and patient perceptions of acceptability of a community-based HCV test-and-treat intervention within ACCHS. METHODS: Semi-structured interviews were undertaken with 23 patient participants and 14 healthcare personnel (including Aboriginal Health Workers/Practitioners, nurses, general practitioners, and practice managers) from across the four ACCHS involved in SCALE-C. A coding framework was developed among study authors and informed by Sekhon's Theoretical Framework of Acceptability. RESULTS: The SCALE-C intervention enabled opportunities for healthcare providers to listen to patients, and for patients to feel heard (affective attitude). HCV testing was opportunistic and often occurred outside of the allocated SCALE-C clinical hours (burden). For patients, HCV testing within SCALE-C was viewed as a moral responsibility and ensured protection of self and others (ethicality). For personnel, SCALE-C (including following up visits) was regarded as an opportunity to engage with patients especially those with complex health needs which may be unrelated to HCV risk factors (ethicality). Patients and personnel widely regarded the SCALE-C intervention to be effective, and the test-and-treat model was preferable for both patients and personnel. CONCLUSION: The SCALE-C intervention was broadly perceived to be acceptable among both healthcare providers and patients within ACCHS. Whilst the prioritisation of HCV was viewed as increasing patient engagement, it was also regarded as an opportunity for addressing other healthcare needs within Aboriginal communities. HCV test-and-treat models of care delivered by ACCHS simplify the HCV care pathway and ensure all HCV care is provided in a culturally safe setting (e.g., patients did not need to attend external services such as pathology).

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation.

BACKGROUND: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). METHODS: We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FINDINGS: Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs. INTERPRETATION: Many smoking-related methylation sites were identified with Illumina's EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FUNDING: Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.

Rashba Metamaterials and Metasurfaces with Zero Reflectivity and Effect of Surface States in Ultrathin Metal Films.

Metals, renowned for their high reflectivity, find extensive use in various technological applications, from mirrors to optical coatings in radars, telescopes, and mobile communications. However, their potential in antireflective coatings has remained largely untapped. In this study, we demonstrate that by applying an ultrathin metallic film onto an oxide layer, we can achieve a flawless optical surface with zero reflectivity. This phenomenon has been successfully observed across various metals, including Sn, Ag, Au, Pt, Bi, and Nb, showcasing its broad applicability. The underlying principle lies in the emergence of surface states, where the Rashba effect is strong, which give rise to the formation of Rashba metamaterial and metasurface (RMM) structures. Remarkably, these RMMs can be fine-tuned to act as high-resolution Veselago lenses. To illustrate, we achieved zero reflectivity with an RMM consisting of a 1 nm thick Sn metal film on a 1 nm Ge buffer, situated on a 60 nm Al2O3/Si substrate. Similar results were observed for other metals (Pt, Au, Ag, and Nb) and semimetals (Bi) by adjusting the film thickness to 2, 3, 5, 10, and 6 nm, respectively. The revelation of RMMs with zero reflectivity (R = 0) has tremendous potential to revolutionize optical device technologies, covering renewable energy, optoelectronics, and the telecommunications industry.

APOBEC3G Is a p53-Dependent Restriction Factor in Respiratory Syncytial Virus Infection of Human Cells Included in the p53/Immune Axis.

Identifying and understanding genetic factors that influence the propagation of the human respiratory syncytial virus (RSV) can lead to health benefits and possibly augment recent vaccine approaches. We previously identified a p53/immune axis in which the tumor suppressor p53 directly regulates the expression of immune system genes, including the seven members of the APOBEC3 family of DNA cytidine deaminases (A3), which are innate immune sentinels against viral infections. Here, we examined the potential p53 and A3 influence in RSV infection, as well as the overall p53-dependent cellular and p53/immune axis responses to infection. Using a paired p53 model system of p53+ and p53- human lung tumor cells, we found that RSV infection activates p53, leading to the altered p53-dependent expression of A3D, A3F, and A3G, along with p53 site-specific binding. Focusing on A3G because of its 10-fold-greater p53 responsiveness to RSV, the overexpression of A3G can reduce RSV viral replication and syncytial formation. We also observed that RSV-infected cells undergo p53-dependent apoptosis. The study was expanded to globally address at the transcriptional level the p53/immune axis response to RSV. Nearly 100 genes can be directly targeted by the p53/immune axis during RSV infection based on our p53BAER analysis (Binding And Expression Resource). Overall, we identify A3G as a potential p53-responsive restriction factor in RSV infection. These findings have significant implications for RSV clinical and therapeutic studies and other p53-influenced viral infections, including using p53 adjuvants to boost the response of A3 genes.

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens.

Mycobacterium tuberculosis, the causative agent of human tuberculosis (hTB), is a close evolutionary relative of Mycobacterium bovis, which causes bovine tuberculosis (bTB), one of the most damaging infectious diseases to livestock agriculture. Previous studies have shown that the pathogenesis of bTB disease is comparable to hTB disease, and that the bovine and human alveolar macrophage (bAM and hAM, respectively) transcriptomes are extensively reprogrammed in response to infection with these intracellular mycobacterial pathogens. In this study, a multi-omics integrative approach was applied with functional genomics and GWAS data sets across the two primary hosts (Bos taurus and Homo sapiens) and both pathogens (M. bovis and M. tuberculosis). Four different experimental infection groups were used: 1) bAM infected with M. bovis, 2) bAM infected with M. tuberculosis, 3) hAM infected with M. tuberculosis, and 4) human monocyte-derived macrophages (hMDM) infected with M. tuberculosis. RNA-seq data from these experiments 24 h post-infection (24 hpi) was analysed using three computational pipelines: 1) differentially expressed genes, 2) differential gene expression interaction networks, and 3) combined pathway analysis. The results were integrated with high-resolution bovine and human GWAS data sets to detect novel quantitative trait loci (QTLs) for resistance to mycobacterial infection and resilience to disease. This revealed common and unique response macrophage pathways for both pathogens and identified 32 genes (12 bovine and 20 human) significantly enriched for SNPs associated with disease resistance, the majority of which encode key components of the NF-κB signalling pathway and that also drive formation of the granuloma.

Mapping pandemic responses in urban Indigenous Australia: Reflections on systems thinking and pandemic preparedness.

OBJECTIVES: We investigate some of the strengths and challenges associated with Covid-19 responses in urban Indigenous communities in Brisbane, Australia. Our research reflects on the interconnected dynamics that impact health outcomes and mitigate or exacerbate the risk of Covid-19 spreading within urban Indigenous communities. METHODS: Three systems thinking workshops were held in 2021 with Indigenous and non-Indigenous stakeholders (N15/workshop) from State and Federal services, along with Aboriginal Community Controlled Health Organisations. All worked in the urban Indigenous health sector. Stakeholders produced a Causal Loop Diagram (CLD) incorporating the critical feedbacks determining the dynamics influencing health outcomes. The aim of the research was to help stakeholders' build awareness of how the structure of the system influences health outcomes. RESULTS: Stakeholders identified 6 key dynamics which have a negative or positive impact on mitigating risks of Covid-19 infection. By mapping these dynamics within a CLD, 7 intervention points were identified. CONCLUSIONS: Systems thinking provides a useful tool in identifying the complexities associated with navigating health challenges, but further research is needed to develop frameworks that work in conjunction with Indigenous Australian methodologies. IMPLICATIONS FOR PUBLIC HEALTH: Indigenous voices and communities must lie central to health responses/policies for Indigenous peoples. When systems thinking is done by or in collaboration with stakeholders it provides a visual language that can help design public health policy. What can be ascertained is that their effectiveness is predicated on systems thinking's integration with Indigenous methodologies that acknowledges Indigenous self-determination and challenges Eurocentric representations of health and Indigeneity.

Proteasome inhibition reprograms chromatin landscape in breast cancer.

The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNAPII transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic super enhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology. Highlights: Proteasome inhibition uncovers de novo Differential Open Chromatin Regions (DOCRs) in breast cancer cells. Proteasome inhibitor sensitive promoters exhibit a distinctive chromatin architecture with discrete transcription initiation patterns.Proteasome inhibition reprograms accessibility of super enhancers.Proteasome inhibitor sensitive super enhancers distinguish basal from non-basal breast cancer subtypes.