Early chromosome condensation by XIST builds A-repeat RNA density that facilitates gene silencing

Valledor, Melvys; Byron, Meg; Dumas, Brett; Carone, Dawn M.; Hall, Lisa L.; Lawrence, Jeanne B.

doi:10.1016/j.celrep.2023.112686

Cited by 4 publications

(2 citation statements)

References 72 publications

(121 reference statements)

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“…In fact, reports suggest there is little difference in the amount of “open chromatin” between the active and inactive X-chromosome (Xa & Xi) (Gilbert et al, 2004; Naughton et al, 2010; reviewed in: Pandya-Jones and Plath, 2016), which was limited to the TSS of silenced genes and thus could not be responsible for the large-scale condensation seen for the BB. In addition, we have previously reported that XIST RNA starts to build the condensed BB structure days before it silences canonical genes (Valledor et al, 2023). Our findings here fit well with this timing difference, since the BB structure is composed of gene-poor, L1-rich DNA rather than gene-rich Alu-rich DNA.…”

Section: Discussionmentioning

confidence: 99%

“…However, why form a “compartment” for silenced genes since epigenetic regulation of promoters is known to provide stable silencing? Insight into this came from a recent study (Valledor et al, 2023) in which we showed that a required step to initiate gene silencing, H3K27 de-acetylation, is a highly unstable step that can be rapidly reversed by histone acetyltransferases (HATs), which are prevalent in active chromatin regions. Results showed that high cytological density of XIST RNA (or small ncRNAs containing the silencing A-repeat domain) was necessary to shift the ongoing balance of HATs and HDACs (Histone deacetylases) toward deacetylation, allowing subsequent epigenetic steps to stabilize the silent state.…”

Section: Discussionmentioning

confidence: 99%

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Differences in Alu vs L1-rich chromosome bands underpin architectural reorganization of the inactive-X chromosome and SAHFs

Hall,

Creamer,

Byron

et al. 2024

Preprint

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The linear DNA sequence of mammalian chromosomes is organized in large blocks of DNA with similar sequence properties, producing a pattern of dark and light staining bands on mitotic chromosomes. Cytogenetic banding is essentially invariant between people and cell-types and thus may be assumed unrelated to genome regulation. We investigate whether large blocks of Alu-rich R-bands and L1-rich G-bands provide a framework upon which functional genome architecture is built. We examine two models of large-scale chromatin condensation: X-chromosome inactivation and formation of senescence-associated heterochromatin foci (SAHFs). XIST RNA triggers gene silencing but also formation of the condensed Barr Body (BB), thought to reflect cumulative gene silencing. However, we find Alu-rich regions are depleted from the L1-rich BB, supporting it is a dense core but not the entire chromosome. Alu-rich bands are also gene-rich, affirming our earlier findings that genes localize at the outer periphery of the BB. SAHFs similarly form within each territory by coalescence of syntenic L1 regions depleted for highly Alu-rich DNA. Analysis of senescent cell Hi-C data also shows large contiguous blocks of G-band and R-band DNA remodel as a segmental unit. Entire dark-bands gain distal intrachromosomal interactions as L1-rich regions form the SAHF. Most striking is that sharp Alu peaks within R-bands resist these changes in condensation. We further show that Chr19, which is exceptionally Alu rich, fails to form a SAHF. Collective results show regulation of genome architecture corresponding to large blocks of DNA and demonstrate resistance of segments with high Alu to chromosome condensation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differences in Alu vs L1-rich chromosome bands underpin architectural reorganization of the inactive-X chromosome and SAHFs

Hall,

Creamer,

Byron

et al. 2024

Preprint

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Trisomy silencing by XIST: translational prospects and challenges

Gupta,

Czerminski,

Lawrence

2024

Hum. Genet.

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XIST RNA is heavily studied for its role in fundamental epigenetics and X-chromosome inactivation; however, the translational potential of this singular RNA has been much less explored. This article combines elements of a review on XIST biology with our perspective on the translational prospects and challenges of XIST transgenics. We first briefly review aspects of XIST RNA basic biology that are key to its translational relevance, and then discuss recent efforts to develop translational utility of XIST for chromosome dosage disorders, particularly Down syndrome (DS). Remarkably, it was shown in vitro that expression of an XIST transgene inserted into one chromosome 21 can comprehensively silence that chromosome and “dosage compensate” Trisomy 21, the cause of DS. Here we summarize recent findings and discuss potential paths whereby ability to induce “trisomy silencing” can advance translational research for new therapeutic strategies. Despite its common nature, the underlying biology for various aspects of DS, including cell types and pathways impacted (and when), is poorly understood. Recent studies show that an inducible iPSC system to dosage-correct chromosome 21 can provide a powerful approach to unravel the cells and pathways directly impacted, and the developmental timing, information key to design pharmacotherapeutics. In addition, we discuss prospects of a more far-reaching and challenging possibility that XIST itself could be developed into a therapeutic agent, for targeted cellular “chromosome therapy”. A few rare case studies of imbalanced X;autosome translocations indicate that natural XIST can rescue an otherwise lethal trisomy. The potential efficacy of XIST transgenes later in development faces substantial biological and technical challenges, although recent findings are encouraging, and technology is rapidly evolving. Hence, it is compelling to consider the transformative possibility that XIST-mediated chromosome therapy may ultimately be developed, for specific pathologies seen in DS, or other duplication disorders.

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The Puzzle of the X: Sex Differences in Autoimmune Diseases

Brown

2024

GEN Biotechnology

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Early chromosome condensation by XIST builds A-repeat RNA density that facilitates gene silencing

Cited by 4 publications

References 72 publications

Differences in Alu vs L1-rich chromosome bands underpin architectural reorganization of the inactive-X chromosome and SAHFs

Differences in Alu vs L1-rich chromosome bands underpin architectural reorganization of the inactive-X chromosome and SAHFs

Trisomy silencing by XIST: translational prospects and challenges

The Puzzle of the X: Sex Differences in Autoimmune Diseases

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