The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells

Abstract

Highlights d CHD8 is expressed at a high level in hematopoietic stem cells (HSCs) d CHD8 loss induces cell cycle arrest, apoptosis, and a differentiation block in HSCs d CHD8 deficiency compromises HSC stemness through activation of p53 target genes d Additional ablation of p53 in CHD8-deficient HSCs restores stem cell function

Unwinding the role of Chd8 helicase in hematopoiesis

“…Although these mice were still pan-cytopenic, phenotypically defined HSCs no longer showed the increased levels of apoptosis observed at earlier stages, and the numbers of immature Lin 2 Sca1 1 Kit 1 progenitors were increased and showed a block in cell-cycle progression in comparison with control mice. 1 Of note, similar results have also been reported by a recent study by Nita et al in Cell Reports, 10 which further shows that, despite the increase in HSPCs, these were still impaired in their reconstitution capacity.…”

“…This idea is also corroborated by experiments performed by Nita et al, where reduced survival was observed when the hematopoietic system of Chd8deficient mice was challenged with the myeloablating drug 5-Fluorouracil. 10 Further studies will be necessary to elucidate the role of Chd8 in stress hematopoiesis and the physiologic relevance of the interaction between Chd8 and ATM.…”

Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

“…Previous studies have revealed a significant role of CHD8 in HSPC maintenance through restricting P53 signaling and loss of P53 restored HSPC survival ( Nita et al, 2021 ; Tu et al, 2021 ). However, the role of CHD8 in mature hematopoietic cell differentiation and whether conditional P53 deletion rescues all the defects caused by CHD8 loss remain unclear.…”

“…Besides its well-known functions of restricting P53 and β-catenin signaling through histone H1 binding, CHD8 is also critical in transcription regulation in neural progenitors and oligodendrocytes ( Durak et al, 2016 ; Nishiyama et al, 2009 ; Sood et al, 2020 ; Thompson et al, 2008 ; Zhao et al, 2018 ). We and others have demonstrated recently that CHD8 is essential for hematopoietic stem/progenitor cell (HSPC) maintenance by restricting P53 signaling ( Nita et al, 2021 ; Tu et al, 2021 ).…”

Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease

“…4 ). For instance, while some are vital for the emergence (CHD1 [ Koh et al 2015 ] and CHD8 [ Shooshtarizadeh et al 2019 ; Nita et al 2021 ; Tu et al 2021 ]) and differentiation of hematopoietic stem and progenitor cells (HSPCs) toward erythroid and myeloid precursors (CHD2) ( Nagarajan et al 2009 ; Varnoosfaderani et al 2020 ), others appear to have an opposing role (CHD7) ( Fig. 4 ; Hsu et al 2013 , 2020 ).…”