The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome

Abstract

The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.

Smchd1is a maternal effect gene required for autosomal imprinting

“…We propose that Smchd1 plays a role in protecting the repressed imprinted genes from inappropriate activation. We and others have previously found that cells without Smchd1 have increased Ctcf binding (26,35,36). At Sm-chd1-sensitive imprinted genes we have found increased H3K4me2 or H3K4me3 (26,29).…”

“…We have discovered Smchd1 is a novel maternal effect gene required for genomic imprinting. Recently, we and others discovered that zygotic Smchd1 mediates long-range chromatin interactions at its target genes, both imprinted regions and elsewhere in the genome (28,35,36). Based on the data presented here, we propose that Smchd1 is required to translate germline imprints into a chromatin state required to silence expression at select imprinted clusters.…”

“…The inactive X also shows an accumulation of polycomb repressive complex 2-mediated histone 3 lysine 27 trimethylation (H3K27me3) in the absence of Smchd1 (28). These data led to a model where Smchd1-mediated chromatin interactions insulate the genome against the action of other epigenetic regulators, such as Ctcf (26,28,35,36); however, it is not known whether this model holds true for all Smchd1 target genes. Based on Smchd1's known role at some imprinted clus-ters (26)(27)(28)(29) and its expression in the oocyte (37), we sought to test the role of oocyte-supplied maternal Sm-chd1 in regulating imprinted gene expression.…”

“…The role of SMCHD1 in normal development and disease has led to an increase in interest in how and when it contributes to gene silencing at each of its genomic targets. Recent work by our group and others has shown that Smchd1 is required for long range chromatin interactions on the inactive X chromosome (28,35,36), and at its autosomal targets including the imprinted loci (28). In cells lacking Smchd1, other epigenetic regulators are enriched at Smchd1 targets, for example, CCCTC-binding factor (Ctcf) binding is enhanced at the inactive X chromosome and the clustered protocadherins (26,35,36).…”

SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres

“…Furthermore, it contains a GHKL (gyrase, Hsp90, histidine kinase, MutL)-type ATPase rather than the bipartite ABC-type ATPase domain typically seen in SMC proteins (Brideau et al, 2015). Several studies implicate roles of SMCHD1 in modulating chromosome architecture at the inactive X chromosome and at Hox clusters (Nozawa et al, 2013;Jansz et al, 2018;Wang et al, 2018;Gdula et al, 2019). SMCHD1 mediates the compaction of the inactive X chromosome in females linking the H3K9me3 and the XIST-H3K27me3 domains (Nozawa et al, 2013).…”