The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells

Abstract

Histone variants contribute to the complexity of the chromatin landscape and play an integral role in defining DNA domains and regulating gene expression. The histone H3 variant H3.3 is incorporated into genic elements independent of DNA replication by its chaperone HIRA. Here we demonstrate that Hira is required for the self-renewal of adult hematopoietic stem cells (HSCs) and to restrain erythroid differentiation. Deletion of Hira led to rapid depletion of HSCs while differentiated hematopoietic cells remained largely unaffected. Depletion of HSCs after Hira deletion was accompanied by increased expression of bivalent and erythroid genes, which was exacerbated upon cell division and paralleled increased erythroid differentiation. Assessing H3.3 occupancy identified a subset of polycomb-repressed chromatin in HSCs that depends on HIRA to maintain the inaccessible, H3.3-occupied state for gene repression. HIRA-dependent H3.3 incorporation thus defines distinct repressive chromatin that represses erythroid differentiation of HSCs.

Acoel single-cell atlas reveals expression dynamics and heterogeneity of a pluripotent stem cell population

“…3 , a histone H3 variant, these cells also express foxO (Fig. S4f), both genes known for their roles in the maintenance, proliferation, and cell cycle control of stem cells in other metazoan lineages (Boehm et al, 2012; Jang et al, 2015; Jullien et al, 2012; Miyamoto et al, 2007; Murdaugh et al, 2021; Sakai et al, 2009; Tothova & Gilliland, 2007; Zhang et al, 2011). These data are suggestive that h3 .…”

“…In addition to having enriched expression of h3.3, a histone H3 variant, these cells also express foxO (Fig. S4f), both genes known for their roles in the maintenance, proliferation, and cell cycle control of stem cells in other metazoan lineages (Boehm et al, 2012;Jang et al, 2015;Jullien et al, 2012;Miyamoto et al, 2007;Murdaugh et al, 2021;Sakai et al, 2009;Tothova & Gilliland, 2007;Zhang et al, 2011). These data are suggestive that h3.3 + cells could represent an unspecialized subset of neoblasts, but further work is needed to rule out the alternative hypotheses including these cells being a temporary cell state that many specialized neoblasts undergo.…”

MicroRNA-221/222-expression in HSC and MPP safeguards their quiescence and multipotency by downregulating stress-independent and dependent expression of IEG and of several myelo/granulopoiesis-enhancing target genes

“…Replication-independent, histone-associated chromatin remodelers ( H3f3b , Hmgb2 , H2afx , H2afz ). Since H3f3b is known to induce erythroid differentiation(58), miR-221/222-dependent upregulation of H3f3b would favor erythroid-myeloid progenitor activation, as seen in our analyses.…”

“…Beyond the known activities of Rgs1 in hypoxia(56) and in SDF-1/CXCR4-induced migration of HSC(57), these genes are expected to contribute to increased erythroid-myeloid differentiation. Replication-independent, histone-associated chromatin remodelers ( H3f3b , Hmgb2 , H2afx , H2afz ). Since H3f3b is known to induce erythroid differentiation(58), miR-221/222-dependent upregulation of H3f3b would favor erythroid-myeloid progenitor activation, as seen in our analyses. We expect, that the combined actions of all of these up-regulated genes could contribute to the activation of HSC from quiescence and to induce selectively increased granulopoiesis(53, 59–62)…”

Transcription-coupled H3.3 recycling: A link with chromatin states

“…Conversely, muscle stem cells in adult mice depend on HIRA to maintain their self-renewal capacity rather than to enable their differentiation [87]. Conflicting dependencies are also reported in the context of hematopoiesis -in some, but not all mouse lineages, HIRA proved critical for transcriptional reprogramming [88,89]. Finally, in hematopoietic transdifferentiation and neuronal differentiation of mESCs, HIRA also proved critical -at early stages, to protect paternal lineage identity, and later on for the successful cell fate change [55].…”