SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X

@article{Wang2018SMCHD1MC,
  title={SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X},
  author={Chen-Yu Wang and Teddy Jégu and Hsueh-Ping Chu and Hyun Jung Oh and Jeannie T. Lee},
  journal={Cell},
  year={2018},
  volume={174},
  pages={406-421.e25}
}

Figures from this paper

The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome
TLDR
It is shown that the non-canonical SMC family protein, SmcHD1, important for developmental gene silencing on Xi, antagonises TAD formation and compartmentalization on the Xi in a transcription independent way.
PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments
TLDR
It is concluded that Xist, PRC1, and SMCHD1 collaborate in an obligatory, sequential manner to partition, fuse, and direct self-association of Xi compartments required for proper spreading of Xist RNA.
Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation
TLDR
A tailor-made mouse iPSC-reprogramming system and high-resolution Hi-C system is combined to produce the first time-course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation, finding that TAD formation precedes transcription, suggesting them to be causally independent.
Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome
TLDR
Whether the conservation of some structural features on the inactive X may reflect selection for X-linked tandem repeats on account of necessary cis- and trans-regulatory roles they may play on the active X, rather than the inactiveX is considered.
Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape
TLDR
Evidence is provided that megadomains do not precede Xist expression or Xi gene silencing, and it is suggested that Dxz4, Firre, and megadamains are dispensable for Xi silencing and escape from X-inactivation.
4D chromosome reconstruction elucidates the spatial reorganization of the mammalian X-chromosome
TLDR
This work uses X-inactivation as a model to examine the time evolution of 3D chromosome architecture during substantial changes in gene expression, and shows that gene expression A/B compartments are consistent with phase separation in 3D space.
Role of the Chromosome Architectural Factor SMCHD1 in X-Chromosome Inactivation, Gene Regulation, and Disease in Humans
TLDR
Overall, this study demonstrates preservation of XCI in arhinia and FSHD2, and implicates SMCHD1 in the regulation of the 3D organization of select autosomal gene clusters.
SmcHD1 underlies the formation of H3K9me3 blocks on the inactive X chromosome in mice
TLDR
The results suggest that SmcHD1 underlies the formation of H3K9me3-enriched blocks on the Xi, which play a critical role in the establishment of the stably silenced state.
Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome
TLDR
The “4DHiC” modeling method is developed to infer 3D information from 2D datasets across time and construct a 3D model of the inactive X-chromosome (Xi), which demonstrates a spatial phase-separation between A/B and S1/S2 compartments to form “hemispheres,” and reveals persistent smaller-scale structures hidden under the Xi superstructure.
...
...

References

SHOWING 1-10 OF 85 REFERENCES
Two independent modes of chromatin organization revealed by cohesin removal
TLDR
It is shown that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding, and the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape.
SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation
TLDR
It is found that SmcHD1 is not required for correct Xist expression, but localizes to the inactiveX and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X, linking a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.
Structural organization of the inactive X chromosome in the mouse
TLDR
A crucial role is demonstrated for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC–seq) and RNA sequencing, and deletion of the boundary disrupts mega-domain formation.
Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture
TLDR
3D mapping, microscopy, and genome editing are combined to study the structure of the inactive X chromosome, focusing on the role of DXZ4, and it is found that superloops and superdomains are conserved across humans, macaque, and mouse.
Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome
TLDR
It is shown that SMCHD1 forms an active GHKL-ATPase homodimer, contrasting with canonical SMC complexes, which exist as tripartite ring structures, and that a parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome.
Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation
TLDR
This model implies that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites, and deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary.
High-resolution Xist binding maps reveal 2-step spreading during X-inactivation
TLDR
High-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq conclude that Xist spreading takes distinct stage-specific forms, but during maintenance, Xist spreads rapidly to both gene-rich and gene-poor regions.
Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation
TLDR
This study reveals, for the first time to the authors' knowledge, where Smchd1 binds genome-wide, its hitherto unappreciated functional interaction with chromatin organizer CCCTC-binding factor in gene regulation, and which part of the protein is required for chromatin binding, which leads to a new model of Smd1 function, where it directly binds DNA to mediate 3D chromatin architecture.
...
...