Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4.

Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.

Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas.

Context: Mutations in the gene encoding Mediator complex subunit MED12 are dominant drivers of uterine fibroids (UFs) in women of diverse racial and ethnic origins. Previously, we showed that UF-linked mutations in MED12 disrupt its ability to activate cyclin C-CDK8/19 in Mediator. However, validation of Mediator kinase disruption in the clinically relevant setting of MED12-mutant UFs is currently lacking. Objective: The objective of this study was twofold. First, to extend the ethnic distribution profile of MED12 mutations by establishing their frequency in UFs from Hispanic women of South Texas. Second, to examine the impact of MED12 mutations on Mediator kinase activity in patient-derived UFs. Methods: We screened 219 UFs from 76 women, including 170 tumors from 57 Hispanic patients, for MED12 exon 2 mutations, and further examined CDK8/19 activity in Mediator complexes immunoprecipitated from MED12 mutation-negative and MED12 mutation-positive UFs. Results: MED12 exon 2 mutations in UFs from Hispanic women are somatic in nature, predominantly monoallelic, and occur at high frequency (54.1%). We identified a minimal cyclin C-CDK8 activation domain on MED12 spanning amino acids 15 through 80 that includes all recorded UF-linked mutations in MED12, suggesting that disruption of Mediator kinase activity is a principal biochemical defect arising from these pathogenic alterations. Analysis of Mediator complexes recovered from patient UFs confirmed this, revealing that Mediator kinase activity is selectively impaired in MED12-mutant UFs. Conclusions: MED12 mutations are important drivers of UF formation in Hispanic women of South Texas. MED12 mutations disrupt Mediator kinase activity, implicating altered CDK8/19 function in UF pathogenesis.

Rethinking the Meaning of Cloud Computing for Health Care: A Taxonomic Perspective and Future Research Directions.

BACKGROUND: Cloud computing is an innovative paradigm that provides users with on-demand access to a shared pool of configurable computing resources such as servers, storage, and applications. Researchers claim that information technology (IT) services delivered via the cloud computing paradigm (ie, cloud computing services) provide major benefits for health care. However, due to a mismatch between our conceptual understanding of cloud computing for health care and the actual phenomenon in practice, the meaningful use of it for the health care industry cannot always be ensured. Although some studies have tried to conceptualize cloud computing or interpret this phenomenon for health care settings, they have mainly relied on its interpretation in a common context or have been heavily based on a general understanding of traditional health IT artifacts, leading to an insufficient or unspecific conceptual understanding of cloud computing for health care. OBJECTIVE: We aim to generate insights into the concept of cloud computing for health IT research. We propose a taxonomy that can serve as a fundamental mechanism for organizing knowledge about cloud computing services in health care organizations to gain a deepened, specific understanding of cloud computing in health care. With the taxonomy, we focus on conceptualizing the relevant properties of cloud computing for service delivery to health care organizations and highlighting their specific meanings for health care. METHODS: We employed a 2-stage approach in developing a taxonomy of cloud computing services for health care organizations. We conducted a structured literature review and 24 semistructured expert interviews in stage 1, drawing on data from theory and practice. In stage 2, we applied a systematic approach and relied on data from stage 1 to develop and evaluate the taxonomy using 14 iterations. RESULTS: Our taxonomy is composed of 8 dimensions and 28 characteristics that are relevant for cloud computing services in health care organizations. By applying the taxonomy to classify existing cloud computing services identified from the literature and expert interviews, which also serves as a part of the taxonomy, we identified 7 specificities of cloud computing in health care. These specificities challenge what we have learned about cloud computing in general contexts or in traditional health IT from the previous literature. The summarized specificities suggest research opportunities and exemplary research questions for future health IT research on cloud computing. CONCLUSIONS: By relying on perspectives from a taxonomy for cloud computing services for health care organizations, this study provides a solid conceptual cornerstone for cloud computing in health care. Moreover, the identified specificities of cloud computing and the related future research opportunities will serve as a valuable roadmap to facilitate more research into cloud computing in health care.

Exploring the Far Side of Mobile Health: Information Security and Privacy of Mobile Health Apps on iOS and Android.

BACKGROUND: Mobile health (mHealth) apps aim at providing seamless access to tailored health information technology and have the potential to alleviate global health burdens. Yet, they bear risks to information security and privacy because users need to reveal private, sensitive medical information to redeem certain benefits. Due to the plethora and diversity of available mHealth apps, implications for information security and privacy are unclear and complex. OBJECTIVE: The objective of this study was to establish an overview of mHealth apps offered on iOS and Android with a special focus on potential damage to users through information security and privacy infringements. METHODS: We assessed apps available in English and offered in the categories "Medical" and "Health & Fitness" in the iOS and Android App Stores. Based on the information retrievable from the app stores, we established an overview of available mHealth apps, tagged apps to make offered information machine-readable, and clustered the discovered apps to identify and group similar apps. Subsequently, information security and privacy implications were assessed based on health specificity of information available to apps, potential damage through information leaks, potential damage through information manipulation, potential damage through information loss, and potential value of information to third parties. RESULTS: We discovered 24,405 health-related apps (iOS; 21,953; Android; 2452). Absence or scarceness of ratings for 81.36% (17,860/21,953) of iOS and 76.14% (1867/2452) of Android apps indicates that less than a quarter of mHealth apps are in more or less widespread use. Clustering resulted in 245 distinct clusters, which were consolidated into 12 app archetypes grouping clusters with similar assessments of potential damage through information security and privacy infringements. There were 6426 apps that were excluded during clustering. The majority of apps (95.63%, 17,193/17,979; of apps) pose at least some potential damage through information security and privacy infringements. There were 11.67% (2098/17,979) of apps that scored the highest assessments of potential damages. CONCLUSIONS: Various kinds of mHealth apps collect and offer critical, sensitive, private medical information, calling for a special focus on information security and privacy of mHealth apps. In order to foster user acceptance and trust, appropriate security measures and processes need to be devised and employed so that users can benefit from seamlessly accessible, tailored mHealth apps without exposing themselves to the serious repercussions of information security and privacy infringements.

Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity.

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at very high frequency (∼70%) in uterine leiomyomas. However, the influence of these mutations on Mediator function and the molecular basis for their tumorigenic potential remain unknown. To clarify the impact of these mutations, we used affinity-purification mass spectrometry to establish the global protein-protein interaction profiles for both wild-type and mutant MED12. We found that uterine leiomyoma-linked mutations in MED12 led to a highly specific decrease in its association with Cyclin C-CDK8/CDK19 and loss of Mediator-associated CDK activity. Mechanistically, this occurs through disruption of a MED12-Cyclin C binding interface that we also show is required for MED12-mediated stimulation of Cyclin C-dependent CDK8 kinase activity. These findings indicate that uterine leiomyoma-linked mutations in MED12 uncouple Cyclin C-CDK8/19 from core Mediator and further identify the MED12/Cyclin C interface as a prospective therapeutic target in CDK8-driven cancers.

Mutations in MED12 cause X-linked Ohdo syndrome.

Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.