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RNA in chromatin (28) | Dr Dave Hartley

Starting with the discovery of the role of Xist RNA in X chromosome inactivation, more RNAs are being discovered associated with chromosome structure and function. This dissertation will explore current knowledge of the significance of RNA in the regulation of chromatin structure and function and how it plays such roles.

Dr Dave Hartley


The dynamic changes of X chromosome inactivation during early culture of human embryonic stem cells

Abstract: X chromosome inactivation (XCI) is required for dosage compensation of X-linked genes in human female cells. Several previous reports have described the promiscuous XCI status in long-term cultured female human embryonic stem cells (hESCs), and the majority of them exhibit non-random XCI. However, when and how such female hESCs acquire the aberrant XCI states during culture is unknown. Herein, through comparing the XCI states in 18 paired hES cell lines throughout early culture, we revealed a uniform dynamic change during this culture period under a widely used culture condition. The female initial hESCs (ihESCs, < P5) expressed XIST RNA, H3K27me3 punctate enrichment and displayed random XCI pattern. By further culturing, the female early hESCs (ehESCs, P20–P30) lost the expression of XIST RNA, H3K27me3 punctate enrichment and exhibited a completely skewed XCI pattern. Importantly, a subset of X-linked genes was up-regulated in ehESCs, including some cancer-related genes. At last, we found 5% physiological oxygen was beneficial for the expression of XIST and H3K27me3 punctate enrichment, but not for the XCI pattern. We conclude that the XCI dynamic change is a frequent epigenetic instability event during early culture, which is accompanied by the up-regulation of some X-linked genes. Furthermore, we emphasize that physiological oxygen is beneficial for XCI fidelity.

Pub.: 22 May '16, Pinned: 25 Jan '17

A Tale of Two Cities: How Xist and its partners localize to and silence the bicompartmental X

Abstract: Sex chromosomal dosage compensation in mammals takes the form of X chromosome inactivation (XCI), driven by the non-coding RNA Xist. In contrast to dosage compensation systems of flies and worms, mammalian XCI has to restrict its function to the Xist-producing X chromosome, while leaving autosomes and active X untouched. The mechanisms behind the long-range yet cis-specific localization and silencing activities of Xist have long been enigmatic, but genomics, proteomics, super-resolution microscopy, and innovative genetic approaches have produced significant new insights in recent years. In this review, I summarize and integrate these findings with a particular focus on the redundant yet mutually reinforcing pathways that enable long-term transcriptional repression throughout the soma. This includes an exploration of concurrent epigenetic changes acting in parallel within two distinct compartments of the inactive X. I also examine how Polycomb repressive complexes 1 and 2 and macroH2A may bridge XCI establishment and maintenance. XCI is a remarkable phenomenon that operates across multiple scales, combining changes in nuclear architecture, chromosome topology, chromatin compaction, and nucleosome/nucleotide-level epigenetic cues. Learning how these pathways act in concert likely holds the answer to the riddle posed by Cattanach’s and other autosomal translocations: What makes the X especially receptive to XCI?

Pub.: 09 Apr '16, Pinned: 25 Jan '17