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1.
J Exp Med ; 221(5)2024 May 06.
Article in English | MEDLINE | ID: mdl-38497819

ABSTRACT

The mycobiota are a critical part of the gut microbiome, but host-fungal interactions and specific functional contributions of commensal fungi to host fitness remain incompletely understood. Here, we report the identification of a new fungal commensal, Kazachstania heterogenica var. weizmannii, isolated from murine intestines. K. weizmannii exposure prevented Candida albicans colonization and significantly reduced the commensal C. albicans burden in colonized animals. Following immunosuppression of C. albicans colonized mice, competitive fungal commensalism thereby mitigated fatal candidiasis. Metagenome analysis revealed K. heterogenica or K. weizmannii presence among human commensals. Our results reveal competitive fungal commensalism within the intestinal microbiota, independent of bacteria and immune responses, that could bear potential therapeutic value for the management of C. albicans-mediated diseases.


Subject(s)
Candidiasis , Gastrointestinal Microbiome , Humans , Animals , Mice , Symbiosis , Immunosuppression Therapy
2.
Nature ; 611(7937): 674-675, 2022 11.
Article in English | MEDLINE | ID: mdl-36385283
3.
Cell ; 185(20): 3789-3806.e17, 2022 09 29.
Article in English | MEDLINE | ID: mdl-36179670

ABSTRACT

Cancer-microbe associations have been explored for centuries, but cancer-associated fungi have rarely been examined. Here, we comprehensively characterize the cancer mycobiome within 17,401 patient tissue, blood, and plasma samples across 35 cancer types in four independent cohorts. We report fungal DNA and cells at low abundances across many major human cancers, with differences in community compositions that differ among cancer types, even when accounting for technical background. Fungal histological staining of tissue microarrays supported intratumoral presence and frequent spatial association with cancer cells and macrophages. Comparing intratumoral fungal communities with matched bacteriomes and immunomes revealed co-occurring bi-domain ecologies, often with permissive, rather than competitive, microenvironments and distinct immune responses. Clinically focused assessments suggested prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers, and synergistic predictive performance with bacteriomes.


Subject(s)
Mycobiome , Neoplasms , DNA, Fungal/analysis , Fungi/genetics , Humans
4.
Oncoimmunology ; 9(1): 1800957, 2020 07 29.
Article in English | MEDLINE | ID: mdl-32934891

ABSTRACT

Many characteristics of cancer such as proliferation, survival, progression, immunogenicity, sensitivity, and resistance to therapy are not just endogenously driven by the tumor cells themselves, but are greatly affected by their interaction with the components of their microenvironment. In our recent report, we comprehensively characterized the bacterial content of solid tumors, which is strongly related to tumor type and subtype, largely presenting as metabolically-active and intra-cellular. Our integration with clinical patient data indicates potential avenues of cross-talk between the tumors and their bacterial counterparts paving the way for a deeper understanding of the physiological/biological context of the tumor and how to harness bacteria in therapy settings.


Subject(s)
Microbiota , Neoplasms , Bacteria/genetics , Humans , Tumor Microenvironment
5.
Science ; 368(6494): 973-980, 2020 05 29.
Article in English | MEDLINE | ID: mdl-32467386

ABSTRACT

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.


Subject(s)
Bacteria/classification , Microbiota , Neoplasms/microbiology , Bacteria/genetics , Bacteria/isolation & purification , Breast/microbiology , Colon/microbiology , Female , Humans , Immunotherapy , Lung/microbiology , Macrophages/microbiology , Male , Neoplasms/therapy , Ovary/microbiology , RNA, Ribosomal, 16S/genetics
6.
Nucleic Acids Res ; 44(9): 4080-9, 2016 05 19.
Article in English | MEDLINE | ID: mdl-27084933

ABSTRACT

Pluripotent self-renewing embryonic stem cells (ESCs) have been the focus of a growing number of high-throughput experiments, revealing the genome-wide locations of hundreds of transcription factors and histone modifications. While most of these datasets were used in a specific context, all datasets combined offer a comprehensive view of chromatin characteristics and regulatory elements that govern cell states. Here, using hundreds of datasets in ESCs, we generated colocalization maps of chromatin proteins and modifications, and built a discovery pipeline for regulatory proteins of gene families. By comparing genome-wide binding data with over-expression and knockdown analysis of hundreds of genes, we discovered that the pluripotency-related factor NR5A2 separates mitochondrial from cytosolic ribosomal genes, regulating their expression. We further show that genes with a common chromatin profile are enriched for distinct Gene Ontology (GO) categories. Our approach can be generalized to reveal common regulators of any gene group; discover novel gene families, and identify common genomic elements based on shared chromatin features.


Subject(s)
Chromatin/genetics , Human Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/cytology , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Binding Sites , Cell Differentiation/genetics , Histones/genetics , Humans , Mice , Mitochondrial Ribosomes/metabolism , Ribosomal Proteins/genetics , Transcription Factors/metabolism
8.
Cell Rep ; 10(12): 2019-31, 2015 Mar 31.
Article in English | MEDLINE | ID: mdl-25818293

ABSTRACT

Embryonic stem cells (ESCs) possess a distinct chromatin conformation maintained by specialized chromatin proteins. To identify chromatin regulators in ESCs, we developed a simple biochemical assay named D-CAP (differential chromatin-associated proteins), using brief micrococcal nuclease digestion of chromatin, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Using D-CAP, we identified several differentially chromatin-associated proteins between undifferentiated and differentiated ESCs, including the chromatin remodeling protein SMARCD1. SMARCD1 depletion in ESCs led to altered chromatin and enhanced endodermal differentiation. Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses suggested that SMARCD1 is both an activator and a repressor and is enriched at developmental regulators and that its chromatin binding coincides with H3K27me3. SMARCD1 knockdown caused H3K27me3 redistribution and increased H3K4me3 around the transcription start site (TSS). One of the identified SMARCD1 targets was Klf4. In SMARCD1-knockdown clones, KLF4, as well as H3K4me3 at the Klf4 locus, remained high and H3K27me3 was abolished. These results propose a role for SMARCD1 in restricting pluripotency and activating lineage pathways by regulating H3K27 methylation.


Subject(s)
Cell Differentiation/genetics , Cell Differentiation/physiology , Chromatin/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Gene Expression Regulation, Developmental/genetics , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolism , Animals , Histones/metabolism , Jumonji Domain-Containing Histone Demethylases/genetics , Kruppel-Like Factor 4 , Mice
9.
Nat Cell Biol ; 15(10): 1139-40, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24084863

ABSTRACT

The role of RNA splicing in the regulation of stem cell properties has remained largely unexplored. The splicing-associated protein SON is now shown to be necessary for embryonic stem cell maintenance, by influencing the splicing of pluripotency regulators.


Subject(s)
DNA-Binding Proteins/metabolism , Pluripotent Stem Cells/metabolism , RNA Splicing/physiology , Embryonic Stem Cells/metabolism , Humans , Minor Histocompatibility Antigens
11.
Nucleic Acids Res ; 41(12): 6300-15, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23630323

ABSTRACT

The transcriptional landscape in embryonic stem cells (ESCs) and during ESC differentiation has received considerable attention, albeit mostly confined to the polyadenylated fraction of RNA, whereas the non-polyadenylated (NPA) fraction remained largely unexplored. Notwithstanding, the NPA RNA super-family has every potential to participate in the regulation of pluripotency and stem cell fate. We conducted a comprehensive analysis of NPA RNA in ESCs using a combination of whole-genome tiling arrays and deep sequencing technologies. In addition to identifying previously characterized and new non-coding RNA members, we describe a group of novel conserved RNAs (snacRNAs: small NPA conserved), some of which are differentially expressed between ESC and neuronal progenitor cells, providing the first evidence of a novel group of potentially functional NPA RNA involved in the regulation of pluripotency and stem cell fate. We further show that minor spliceosomal small nuclear RNAs, which are NPA, are almost completely absent in ESCs and are upregulated in differentiation. Finally, we show differential processing of the minor intron of the polycomb group gene Eed. Our data suggest that NPA RNA, both known and novel, play important roles in ESCs.


Subject(s)
Cell Differentiation/genetics , Embryonic Stem Cells/metabolism , Pluripotent Stem Cells/metabolism , RNA, Small Untranslated/metabolism , Transcription, Genetic , Animals , Cells, Cultured , Epigenesis, Genetic , Histones/genetics , Male , Mice , Proteins/genetics , RNA Polymerase II/metabolism , RNA Splicing , RNA, Small Untranslated/biosynthesis , RNA, Small Untranslated/physiology , Spliceosomes/metabolism
12.
Nat Struct Mol Biol ; 20(1): 119-26, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23222641

ABSTRACT

Histones, the building blocks of eukaryotic chromatin, are essential for genome packaging, function and regulation. However, little is known about their transcriptional regulation. Here we conducted a comprehensive computational analysis, based on chromatin immunoprecipitation-sequencing and -microarray analysis (ChIP-seq and ChIP-chip) data of over 50 transcription factors and histone modifications in mouse embryonic stem cells. Enrichment scores supported by gene expression data from gene knockout studies identified E2f1 and E2f4 as master regulators of histone genes, CTCF and Zfx as repressors of core and linker histones, respectively, and Smad1, Smad2, YY1 and Ep300 as restricted or cell type-specific regulators. We propose that histone gene regulation is substantially more complex than previously thought, and that a combination of factors orchestrate histone gene regulation, from strict synchronization with S phase to targeted regulation of specific histone subtypes.


Subject(s)
Chromatin/genetics , Gene Expression Regulation , Histones/genetics , Transcription Factors/metabolism , Animals , Binding Sites , CCCTC-Binding Factor , Chromatin/metabolism , Chromatin Immunoprecipitation , E1A-Associated p300 Protein/metabolism , E2F1 Transcription Factor/metabolism , E2F4 Transcription Factor/metabolism , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Kruppel-Like Transcription Factors/metabolism , Mice , Oligonucleotide Array Sequence Analysis , Repressor Proteins/metabolism , Sequence Analysis, DNA , Smad1 Protein/metabolism , Smad2 Protein/metabolism , Transcription, Genetic , YY1 Transcription Factor/metabolism
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