Kinkel Sarah A, Liu Joy, Beck Tamara, Breslin Kelsey A, Iminitoff Megan, Hickey Peter, Blewitt Marnie E
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
The Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
iScience. 2022 Jun 30;25(7):104684. doi: 10.1016/j.isci.2022.104684. eCollection 2022 Jul 15.
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 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. -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 -deleted females, which showed a loss of quiescent HSCs and fewer B cells. Gene expression profiling of -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.
SMCHD1（含染色体结构维持铰链结构域1）是一种非典型的SMC蛋白，可介导长程抑制性染色质结构。女性细胞中的X染色体失活以及印记和聚集的常染色体基因的抑制都需要SMCHD1，其突变与人类疾病面肩肱型肌营养不良（FSHD）和博斯马无鼻小眼综合征（BAMS）有关。我们使用条件性小鼠模型来研究造血过程中的SMCHD1。SMCHD1缺失的小鼠尽管在竞争性骨髓移植中显示出重建能力受损以及与年龄相关的造血干细胞（HSC）丢失，但仍维持稳态造血。这种表型在SMCHD1缺失的雌性小鼠中更为明显，它们表现出静止期造血干细胞的丢失和较少的B细胞。对SMCHD1缺陷的造血干细胞和B细胞进行基因表达谱分析，揭示了已知的和细胞类型特异性的对SMCHD1敏感的基因，以及雌性细胞中X连锁基因表达的显著破坏。这些数据表明SMCHD1是造血干细胞的调节因子，其作用在雌性中更为显著。
