Abstract
The interplay between polycomb and trithorax complexes has been implicated in embryonic stem cell (ESC) self-renewal and differentiation. It has been shown recently that WRD5 and Dpy-30, specific components of the SET1/MLL protein complexes, play important roles during ESC self-renewal and differentiation of neural lineages. However, not much is known about how and where specific trithorax complexes are targeted to genes involved in self-renewal or lineage-specification. Here, we report that the recruitment of the hSET1A histone H3K4 methyltransferase (HMT) complex by transcription factor USF1 is required for mesoderm specification and lineage differentiation. In undifferentiated ESCs, USF1 maintains hematopoietic stem/progenitor cell (HS/PC) associated bivalent chromatin domains and differentiation potential. Furthermore, USF1 directed recruitment of the hSET1A complex to the HoxB4 promoter governs the transcriptional activation of HoxB4 gene and regulates the formation of early hematopoietic cell populations. Disruption of USF or hSET1A function by overexpression of a dominant-negative AUSF1 mutant or by RNA-interference-mediated knockdown, respectively, led to reduced expression of mesoderm markers and inhibition of lineage differentiation. We show that USF1 and hSET1A together regulate H3K4me3 modifications and transcription preinitiation complex assembly at the hematopoietic-associated HoxB4 gene during differentiation. Finally, ectopic expression of USF1 in ESCs promotes mesoderm differentiation and enforces the endothelial-to-hematopoietic transition by inducing hematopoietic-associated transcription factors, HoxB4 and TAL1. Taken together, our findings reveal that the guided-recruitment of the hSET1A histone methyltransferase complex and its H3K4 methyltransferase activity by transcription regulator USF1 safeguards hematopoietic transcription programs and enhances mesoderm/hematopoietic differentiation.
Highlights
Embryonic stem cells (ESCs) have the ability to differentiate into any cell type of the body and offer a great tool for studying processes involved in cellular differentiation
We demonstrate that DNA binding factor USF1 interacts with and brings the hSET1A enzymatic complex to its target gene, HoxB4, during blood cell specification and differentiation
Consistent with the function of HoxB4 in early blood cell formation, we found that the inactivation of USF1 or hSET1A activities leads to a block in the differentiation of blood cells and causes reductions in methylation levels of H3K4 and expression of HoxB4, without impairing the selfrenewal capability of ESCs
Summary
Embryonic stem cells (ESCs) have the ability to differentiate into any cell type of the body and offer a great tool for studying processes involved in cellular differentiation. To maintain the stemness properties of ESCs, pluripotency associated genes such as Oct, Sox, and Nanog are marked by high levels of H3K4me whereas many silenced lineage-specific genes are either marked by bivalent H3K4me3/ H3K27me or by H3K27me alone [3,4,5,6,7,8,9]. Bivalent domains, a unique chromatin feature of stem cells and some differentiated cell lineages, mark developmental genes that are primed to be activated [2]. It has been suggested that both polycomb (PcG) and trithorax (TrxG) group complexes play an important role in ESC self-renewal and differentiation [7,8,11,12], the mechanisms by which specific TrxG proteins and the modification of H3K4me are targeted to specific gene loci and initiate differentiation of particular cell lineages still remain unknown
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