Biology subjects

Bilenky, M.

Publications and source records attributed to Bilenky, M..

7 recordsLinked to original sources

bioRxiv2026

EpiATLAS - a reference for human epigenomic research

The sequence of the human genome provides a foundation for understanding cellular processes in health and disease1. The organisation of this primary genetic information into cell-specific structure and function is critical to understanding the cell type-specific interpretation and execution of the genome. Epigenetic processes are essential for packaging and higher-level functional organisation of the genome, and changes therein are increasingly recognised as contributors to human disease. Building on primary data generated by multinational consortia, the International Human Epigenome Consortium2 (IHEC) has uniformly processed a collection of more than 2000 comprehensive human reference epigenomes, collectively referred to as EpiATLAS. This effort involved the development of standardised molecular and bioinformatics protocols, metadata models, and analytical tools to manage, integrate, display, and share vast amounts of epigenomic data. This includes the creation of a publicly available Epigenome Reference Registry, which provides a system for accessing protected human subject datasets and facilitates open searching of de-identified samples and experimental data. The integrated EpiATLAS ecosystem and its comprehensive human reference epigenome maps provide an unprecedented resource for the biosciences, expanding the annotated epigenomic landscape while uncovering previously unappreciated relationships among regulatory layers and revealing how epigenetic inputs underpin fundamental cellular functions and disease associations.

genomics↗

bioRxiv2025

Cell type-specific epigenomic variation and its association with genotype in the human breast

BackgroundUnderstanding the interplay between genomic variation and the epigenome is fundamental to the study of development and mechanisms of disease. Previous studies have leveraged population-scale genotype surveys to associate alleles with epigenomic states in heterogenous tissue types. However, epigenomes are inherently cell type-specific, giving rise to unique genome-epigenome interactions that can influence distinct functional states and susceptibility to disease. Moreover, the extent of individual variation in cell type-specific epigenotypes remains poorly understood, posing additional challenges to accurately link genotypes with epigenomic features. ResultsWe generated comprehensive genomic and epigenomic profiles of four functionally defined human breast epithelial cell types from eight healthy individuals. To quantify inter-individual epigenomic variation, we developed a statistical framework that measures variability in histone modification landscapes across individuals. This analysis revealed substantially greater variation in repressive chromatin marked by H3K27me3 than in active chromatin marked by H3K27ac and H3K4me3. Integrative chromatin state analysis further identified enhancer elements as the principal source of epigenomic divergence between individuals. Stable enhancer states corresponded to high-confidence cis-regulatory elements that underpin cell type-specific transcriptional programs, whereas variable enhancer states were enriched for environmentally responsive regulatory circuits. Mapping genetic variants associated with chromatin state variation uncovered extensive cell type-specificity, with nearly 90% of regulatory variants detected in only a single cell type. These associations were strongly enriched within active regulatory chromatin and, when integrated with gene expression, enabled the prioritization of functional regulatory variants. We experimentally validated one such variant, rs75071948, demonstrating allele-specific regulation of ANXA1 expression using CRISPR/Cas9 genome editing. ConclusionsOur study defines the landscape of normal epigenomic variation across the major human breast epithelial cell types and demonstrates that genome-epigenome interactions are highly cell type-specific. These findings establish cell type as a critical determinant of the functional interpretation of regulatory genetic variation and provide a framework for understanding how inherited genetic variation shapes normal breast biology and disease susceptibility.

genomics↗

bioRxiv2024

Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming

Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.

cancer biology↗

bioRxiv2020

Dynamics of the cell-free DNA methylome of metastatic castration resistant prostate cancer during androgen-targeting treatment

AimWe examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment. Materials and MethodsGenome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. ResultsAlterations in methylation states previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression (TTP). Importantly, we also report that markers associated with a highly aggressive form of the disease, Neuroendocrine-CRPC, were associated with a faster TTP. ConclusionOur findings highlight the potential of monitoring cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

cancer biology↗

bioRxiv2020

The pathognomonic FOXL2 C134W mutation alters DNA binding specificity

The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumours (AGCT) and a diagnostic marker for this tumour type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore the mechanisms driving FOXL2C134W pathogenicity we engineered V5-FOXL2WT and V5-FOXL2C134W inducible isogenic cell lines and performed ChIP-seq and transcriptome profiling. We found that FOXL2C134W associates with the majority of the FOXL2 WT DNA elements as well as a large collection of unique elements genome-wide. We confirmed an altered DNA binding specificity for FOXL2C134W in vitro and identified unique targets of FOXL2C134W including SLC35F2 whose expression increased sensitivity to YM155 in our model. Statement of SignificanceMechanistic understanding of FOXL2C134W induced regulatory state alterations drives discovery of a rationally designed therapeutic strategy.

cancer biology↗

bioRxiv2019

Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs

Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. We now show that the more primitive types of human cells in this system display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in terminally differentiated monocytes and erythroblasts. Additional intervention data implicate that control of this chromatin state change is a requisite part of the process, whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.

cell biology↗

bioRxiv2019

Genetic dissection of the redundant and divergent functions of histone chaperone paralogs in yeast

Gene duplications increase organismal robustness by providing freedom for gene divergence or by increasing gene dosage. The yeast histone chaperones Fpr3 and Fpr4 are paralogs that can assemble nucleosomes in vitro, however the genomic locations they target and their functional relationship is poorly understood. We refined the yeast synthetic genetic array (SGA) approach to enable the functional dissection of gene paralogs. Applying this method to Fpr3 and Fpr4 uncovered their redundant and divergent functions: while Fpr3 is uniquely involved in chromosome segregation, Fpr3 and Fpr4 co-operate on some genes and are redundant on others where they impact gene expression and transcriptional processivity. We find that the TRAMP5 RNA exosome is essential in{Delta} fpr3{Delta}fpr4 yeast and leverage this information to identify Fpr3/4 target loci. Amongst these are the non-transcribed spacers of ribosomal DNA where either paralog is sufficient to establish chromatin that is both transcriptionally silent and refractory to recombination. These data provide evidence that Fpr3 and Fpr4 have shared chromatin-centric functions, especially at nucleolar rDNA. However, their distinct genetic interaction profiles show they also have evolved separate functions outside of the nucleolus.

genetics↗