Structure of Nascent Chromatin Is Essential for Hematopoietic Lineage Specification

Abstract

Summary The role of chromatin structure in lineage commitment of multipotent hematopoietic progenitors (HPCs) is presently unclear. We show here that CD34+ HPCs possess a post-replicative chromatin globally devoid of the repressive histone mark H3K27me3. This H3K27-unmodified chromatin is required for recruitment of lineage-determining transcription factors (TFs) C/EBPα, PU.1 and GATA-1 to DNA just after DNA replication upon cytokine-induced myeloid or erythroid commitment. Blocking DNA replication or increasing H3K27me3 levels prevents recruitment of these TFs to DNA and suppresses cytokine-induced erythroid or myeloid differentiation. However, H3K27me3 is rapidly associated with nascent DNA in more primitive human and murine HPCs. Treatment of these cells with instructive cytokines leads to a significant delay in accumulation of H3K27me3 in nascent chromatin due to activity of the H3K27me3 demethylase UTX. Thus, HPCs utilize special mechanisms of chromatin modification for recruitment of specific TFs to DNA during early stages of lineage specification.

Delayed Accumulation of H3K27me3 on Nascent DNA Is Essential for Recruitment of Transcription Factors at Early Stages of Stem Cell Differentiation

“…The newly found decondensed structure of post-replicative chromatin and its importance for acquiring differentiation signals in the form of binding of key TFs to DNA are likely the features of not only pluripotent but also multipotent cells, like hematopoietic blood progenitor cells, HPCs (Petruk, 2017). Interestingly, the overall features of the open, H3K27me3-lacking chromatin are essentially the same in induced m/hESCs and HPCs, suggesting that this may be a general feature of all differentiating eukaryotic stem cells.…”

The changing face of hematopoiesis: a spectrum of options is available to stem cells

“…One piece of evidence that a continuum of options is open to HSC is that just after cell division the chromatin of human CD34 + HPC is completely devoid of the repressive histone mark H3K27me3. In terms of the timing of the recruitment of the transcription factors that play a key role in regulating myeloid (C/EBPα, PU.1) versus erythroid (GATA‐1) differentiation (Figure ) this aspect of chromatin structure is important for lineage specification. Arinobu and colleagues have argued that activation of PU.1 and GATA‐1 within HSC specifies myeloid/lymphoid versus myeloid/erythroid fates, respectively .…”

“…Upon treatment of CD34 + HPC with G‐CSF/M‐CSF and Epo, the appropriate lineage‐affiliated transcription factors (see above) are recruited to DNA just after DNA replication. Cytokine‐driven differentiation was suppressed by increasing H3K27me3 levels or blocking DNA replication . A caveat to the above is that by demonstrating that random PU.1 to GATA‐1 protein ratios do not initiate lineage choice, Hoppe and colleagues have argued that PU.1 and GATA‐1 merely reinforce a choice that has already been made .…”

Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs

“…Epigenetic mechanisms play a central role in hematopoietic cell fate decisions [27][28][29][30][31][32] . Of particular interest here is the repressive H3K27me3 chromatin modification that has been implicated in the regulation of hematopoiesis in vivo and in vitro [33][34][35][36][37] and how manipulation of H3K27me3 may impact the steps progenitors undergo to produce mature myeloid and lymphoid cell types 35,38 . Both overexpression and inactivation of PRC2 components, responsible for the methylation of H3K27 have been reported in hematopoietic malignancies, further reinforcing the importance of H3K27me3 in regulating normal hematopoiesis 39,40 .…”