Epigenetic modifier SMCHD1 maintains a normal pool of long-term hematopoietic stem cells

Sarah A Kinkel; Joy Liu; Tamara Beck; Kelsey A Breslin; Megan Iminitoff; Peter Hickey; Marnie E Blewitt

doi:10.1016/j.isci.2022.104684

Epigenetic modifier SMCHD1 maintains a normal pool of long-term hematopoietic stem cells

iScience. 2022 Jun 30;25(7):104684. doi: 10.1016/j.isci.2022.104684. eCollection 2022 Jul 15.

Authors

Sarah A Kinkel^{1

2}, Joy Liu^{1

2}, Tamara Beck¹, Kelsey A Breslin¹, Megan Iminitoff^{1

2}, Peter Hickey^{1

2}, Marnie E Blewitt^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
² The Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.

Abstract

SMCHD1 (structural maintenance of chromosomes hinge domain containing 1) is a noncanonical SMC protein that mediates long-range repressive chromatin structures. SMCHD1 is required for X chromosome inactivation in female cells and repression of imprinted and clustered autosomal genes, with SMCHD1 mutations linked to human diseases facioscapulohumeral muscular dystrophy (FSHD) and bosma arhinia and micropthalmia syndrome (BAMS). We used a conditional mouse model to investigate SMCHD1 in hematopoiesis. Smchd1-deleted mice maintained steady-state hematopoiesis despite showing an impaired reconstitution capacity in competitive bone marrow transplantations and age-related hematopoietic stem cell (HSC) loss. This phenotype was more pronounced in Smchd1-deleted females, which showed a loss of quiescent HSCs and fewer B cells. Gene expression profiling of Smchd1-deficient HSCs and B cells revealed known and cell-type-specific SMCHD1-sensitive genes and significant disruption to X-linked gene expression in female cells. These data show SMCHD1 is a regulator of HSCs whose effects are more profound in females.

Keywords: Cell biology; Developmental biology; Molecular biology; Stem cells research.