Showing papers by "Eran Meshorer published in 2016"

The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

Abstract: INTRODUCTION Cancer arises from clonal expansion of a single cell. Yet, most human cancers are characterized by extensive intratumor heterogeneity and comprise various subpopulations of cells with distinct phenotypes and biological properties. Intratumor heterogeneity poses major challenges in understanding cancers, managing patients, and designing effective treatment strategies. Functional heterogeneity within individual tumors is partly due to the presence of genetically distinct subclonal cell populations. Furthermore, interactions between cancer cells and the tumor microenvironment can alter the phenotype of cancer cells via nongenetic mechanisms. The combination of cell-intrinsic and cell-extrinsic changes occurring during tumor growth generates functionally distinct subsets of cells that differentially contribute to tumor maintenance. RATIONALE In many cancers, phenotypic and functional heterogeneity can be mapped to distinct differentiation states, suggesting that cellular hierarchies established during tumor growth may affect the long-term proliferative potential of cancer cells. To shed light on the mechanisms responsible for the generation of these hierarchies, we searched for epigenetic mechanisms that determine which cancer cells can preserve unlimited proliferative potential, and thus the ability to drive long-term tumor growth, and which cells lose this ability through a differentiation process. RESULTS We found that, in several cancer types, individual tumors exhibit high heterogeneity of the major chromatin protein linker histone H1.0, showing strongly reduced H1.0 levels in cells characterized by long-term self-renewal ability and tumorigenic potential and higher levels in nontumorigenic cells. Combined analysis of pan-cancer patient data sets and experimental alteration of the H1F0 locus in tumor cells revealed that heterogeneous H1.0 expression patterns are partly due to differential methylation of an enhancer region that dynamically modulates H1.0 expression within tumors. Using a controlled system to model functional intratumor heterogeneity, we showed that maintenance of cell tumorigenic potential required silencing of H1.0 to avoid loss of unlimited proliferative capacity through differentiation. Mechanistically, absence of H1.0 led to destabilization of nucleosome-DNA interactions in AT-rich genomic regions and coordinated derepression of large sets of neighboring genes, resulting in activation of transcriptional programs that support cancer cell self-renewal. Gene expression changes induced by H1.0 loss were reversible, and epigenetic states restricting cell proliferative potential were reestablished upon H1.0 reexpression. In multiple cancer types, in agreement with the observed inhibition of cancer cell self-renewal by H1.0, patients expressing overall strongly reduced levels of H1.0 showed a significantly worse outcome than patients expressing higher H1.0 levels. CONCLUSION Intratumor heterogeneity has emerged as a general feature of cancer, but the molecular features underlying functionally diverse cellular phenotypes have been elusive. Our results uncover epigenetic determinants of tumor-maintaining cells and identify an integral component of chromatin as an important regulator of cell differentiation states within tumors. We propose that only cells insensitive to extracellular differentiation cues, capable of permanently silencing H1.0, can act as self-renewing tumor-maintaining cells and that such a mechanism supports maintenance of several types of cancer. Our results suggest that intervention aimed at restoring high levels of H1.0 in all cancer cells may enhance the differentiation process that naturally occurs during tumor growth and may be beneficial for therapeutic purposes.

Epigenetics: It's Getting Old. Past Meets Future in Paleoepigenetics

Abstract: Recent years have witnessed the rise of ancient DNA (aDNA) technology, allowing comparative genomics to be carried out at unprecedented time resolution. While it is relatively straightforward to use aDNA to identify recent genomic changes, it is much less clear how to utilize it to study changes in epigenetic regulation. Here we review recent works demonstrating that highly degraded aDNA still contains sufficient information to allow reconstruction of epigenetic signals, including DNA methylation and nucleosome positioning maps. We discuss challenges arising from the tissue specificity of epigenetics, and show how some of them might in fact turn into advantages. Finally, we introduce a method to infer methylation states in tissues that do not tend to be preserved over time.

Epigenetics: It's Getting Old. Past Meets Future in

Abstract: RecentyearshavewitnessedtheriseofancientDNA(aDNA)technology,allowing comparative genomics to be carried out at unprecedented time resolution. While itisrelativelystraightforwardtouseaDNAtoidentifyrecentgenomicchanges,itis muchlessclearhowtoutilizeittostudychangesinepigeneticregulation.Herewe review recent works demonstrating that highly degraded aDNA still contains sufficient information to allow reconstruction of epigenetic signals, including DNA methylation and nucleosome positioning maps. We discuss challenges arising from the tissue specificity of epigenetics, and show how some of them might in fact turn into advantages. Finally, we introduce a method to infer methylation states in tissues that do not tend to be preserved over time. Unearthing Epigenetic Layers The epigenome is viewed today as a collection of regulatory layers that control when, where, and how genes are turned on and off. These layers are passed through cellular or organismal

Systematic identification of gene family regulators in mouse and human embryonic stem cells

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.

Epigenetics in Development, Differentiation and Reprogramming

Abstract: The creation of a complex multicellular organism begins with two haploid cells, the sperm and the egg, merging into one diploid cell. The two genomes are first kept separated as two pronuclei (Cantone and Fisher 2013), but soon thereafter join to form the zygote. This totipotent cell will then go through a series of mitotic cleavage divisions, first creating a small mass of cells called the blastula, and then (by day 3.5 in mouse or day 5.5 in human) form the blastocyst, comprised of the outer trophoblast cells and the pluripotent inner cell mass (ICM). The latter will subsequently differentiate into the three germ layers, creating the new developing organism. During differentiation, each cell expresses a different set of genes, according to its location, function, signaling cascades, etc. Since all cells share the exact same genome, epigenetic processes will dictate the silencing/activation of desired genes, and the maintenance of cellular states.