Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells

Abstract

IntroductionThe murine hematopoietic system is a hierarchically organized process that arises from a small pool of self-renewing hematopoietic stem cells (HSCs). Upon induction of differentiation, HSCs lose self-renewal ability and develop through a series of specialized progenitor cell types that possess restricted differentiation potential. 1 Although several cell-intrinsic and microenvironmental factors that can control these processes have been identified, the precise molecular circuitry controlling HSC self-renewal and lineage restriction has yet to be fully elucidated.Recent observations suggest that epigenetic-based mechanisms play an important role in controlling HSC self-renewal or differentiation. 2,3 Epigenetic regulation of gene expression is largely controlled by the posttranslational modification of histones and DNA methylation, resulting in the alteration of chromatin structure and function at genes throughout cellular differentiation. 4 Core histones can be covalently modified, for example, by acetylation and methylation at multiple residues, offering combinatorial codes with diverse functional outcomes. 5 We and others have hypothesized previously that HSCs possess unique epigenetic signatures, whose inheritance by progenitor subsets allows for differentiation into mature blood cell types via highly coordinated gene activation and silencing. 4,6-9 These unique chromatin states may allow for the preassembling of critical transcription factors at lineage-specifying promoters in HSC and progenitor cells, before full gene expression in differentiated subsets. [10][11][12][13] This process, known as multilineage gene priming, is supported by the low-level transcription of several lineage-affiliated genes of lymphoid, myeloid, and erythroid genetic programs which occurs in HSCs and early progenitor cells. 8,[14][15][16] Most recently, genome-wide profiling of human hematopoietic stem/ progenitor cells and differentiated erythrocyte precursor cells has revealed epigenetic signatures that are proposed to be important for maintaining HSC multipotency. 17 Despite the insights gained from such studies, most have been based on either selected loci or global analysis of cell populations with heterogeneous lineage potentials. As a result, the true epigenetic status of functionally homogeneous stem and progenitor cell compartments may have been underestimated.We have undertaken a global analysis of highly purified and functionally validated murine HSCs, early hematopoietic progenitors, and mature CD4 ϩ T cells to reveal the epigenetic features associated with their unique functional properties. We show that promoters of genes affiliated with regulation of hematopoietic cell maturation are occupied by bivalent histone modifications in HSCs and their immediate progeny. In addition, many lineage-specifying promoters in these primitive cells possess a diverse range of histone modification patterns, together suggesting that specific combinations prepare these genes for selective expression or silencing during linea...

The epigenome of AML stem and progenitor cells

“…Presumably, these promoters are marked by alternate histone modifications such as H3K9me2. These findings are similar to what has been reported so far in hematopoietic stem cells, 36 suggesting that histone modifications regulate gene expression in individual cell population also in AML cells.…”

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

“…4,5 Similarly, the H3K4 methylation status of promoter regions was reported to regulate hematopoietic stem and progenitor multilineage potential and differentiation. [8][9][10] Thus, it is likely that LSD1-kd disturbs hematopoiesis by interfering with the tightly regulated H3K4 methylation status of genes critical for early events in hematopoietic stem and progenitor cell differentiation. Because H3K4 demethylation activity at these promoter regions should be reestablished upon reinstatement of LSD1 expression, we were interested whether normal hematopoiesis returns upon normalization of LSD1 levels.…”

“…2,6,7 The methylation status of the H3K4 and H3K27 residues, composing a so-called bivalent domain, in hematopoietic stem and progenitor cells was shown to be capable of restraining lineage-specific gene expression, while exposing the locus to rapid induction. [8][9][10] Recent in vitro studies have demonstrated that the LSD1 H3K4 demethylating activity is directed to specific genes by the key hematopoietic transcription factors, SCL (also called Tal-1) and Gfi1b. Moreover, in vitro knockdown of LSD1 disturbed hematopoietic differentiation of several cell lines.…”

Classical Hodgkin's lymphoma shows epigenetic features of abortive plasma cell differentiation

“…The specificity and suitability of these antibodies for ChIP were demonstrated in a previously published study. 17,22,23 Details of the protocol are provided in Online Supplementary Protocol S1.…”