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The Inactive X Chromosome Is Folded Like Origami By SMCHD1

The linear molecules of DNA that constitute our genome are wrapped around proteins called histones to form “chromatin.” To fit the nucleus, chromatin must be neatly packaged into organized structures. For instance, mammalian chromosomes are folded into two ‚Äúcompartments‚ÄĚ ‚Äď an active A compartment that contains actively transcribed genes, and an inactive B compartment that harbors mostly genes that are not transcribed. Each compartment is further partitioned into smaller scale structures named ‚Äútopologically associated domains (TADs).‚ÄĚ It is thought that these chromosomal structures play a role in regulating gene expression.

Interestingly, not all mammalian chromosomes are folded into A/B compartments and TADs. X chromosome inactivation, a process that shuts down gene expression on one of the two copies of X chromosomes in female mammals, triggers refolding of inactive X chromosome (Xi) into a unique structure. This Xi-specific structure was previously thought to be without evident compartments and TADs. How the Xi folds in this unique way has been a subject of intense investigation.

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A Massachusetts General Hospital research team in the laboratory of Jeannie T. Lee, MD PhD, began investigating this question by probing the function of a protein named structural maintenance of chromosomes hinge domain containing 1 (SMCHD1).

“We focused on this protein because previous studies found that SMCHD1 is concentrated on the Xi and serves a critical role in the inactivation process, ” remarked Chen-Yu Wang, MD, the lead author in the study. “Furthermore, SMCHD1 is similar to members in the structural maintenance of chromosomes protein family, which is known to be crucial for chromosome folding.”

Using chromosome conformation capture technology, the research team determined the structure of the Xi in female mouse cells lacking SMCHD1. Surprisingly, the Xi in these cells became partitioned into two large compartments ‚ÄĒ in contrast to the ‚Äúcompartment-less‚ÄĚ Xi seen in normal cells. These two compartments, which the team named “S1 and S2 compartments,” are distinct from the A/B compartments found on all other mammalian chromosomes.

The research team further showed that, during X-inactivation, the A/B compartments are first remodeled into S1/S2 compartments. SMCHD1 then binds to S1/S2 compartments and merges them to create the compartment-less Xi.

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“Thus, the Xi is folded in a stepwise manner, a process we likened to origami,” said Jeannie T. Lee, the senior author in the study. “This means that the Xi is far from unstructured. We believe that the unique structure of the Xi is an important part of its biology.”

Indeed, the team went on to show that the stepwise folding of the Xi is critical to suppress gene expression. In cells lacking SMCHD1, about 43% of genes failed to be inactivated. The distribution of Xist, a long noncoding RNA that controls X-inactivation, was also compromised.

In humans, mutations of SMCHD1 are associated with facioscapulohumeral muscular dystrophy, a severe muscle disorder, and Bosma arhinia microphthalmia syndrome, a craniofacial malformation. The finding that SMCHD1 controls chromosome folding suggests that abnormally-folded chromatin may play a role in the pathogenesis in these diseases.

These findings are described in the article entitled SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X, recently published in the journal Cell. This work was conducted by Chen-Yu Wang, Teddy Jégu, Hsueh-Ping Chu, Hyun Jung Oh, and Jeannie T. Lee from Massachusetts General Hospital.

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