Abstract
XIST RNA triggers the transformation of an active X chromosome into a condensed, inactive Barr body and therefore provides a unique window into transitions of higher-order chromosome architecture. Despite recent progress, how XIST RNA localizes and interacts with the X chromosome remains poorly understood. Genetic engineering of XIST into a trisomic autosome demonstrates remarkable capacity of XIST RNA to localize and comprehensively silence that autosome. Thus, XIST does not require X chromosome-specific sequences but operates on mechanisms available genome-wide. Prior results suggested XIST localization is controlled by attachment to the insoluble nuclear scaffold. Our recent work affirms that scaffold attachment factor A (SAF-A) is involved in anchoring XIST, but argues against the view that SAF-A provides a unimolecular bridge between RNA and the chromosome. Rather, we suggest that a complex meshwork of architectural proteins interact with XIST RNA. Parallel work studying the territory of actively transcribed chromosomes suggests that repeat-rich RNA ‘coats’ euchromatin and may impact chromosome architecture in a manner opposite of XIST. A model is discussed whereby RNA may not just recruit histone modifications, but more directly impact higher-order chromatin condensation via interaction with architectural proteins of the nucleus.This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
Highlights
Significant strides have been made in recent years to elucidate the effectors and processes both upstream and downstream of XIST during X chromosome inactivation (XCI) in mammalian females
The model forwarded here is clearly influenced by the concept of an insoluble, non-chromatin nuclear scaffolding, termed the nuclear matrix, which we recognize remains somewhat controversial or not fully established
We assert that properties of XIST RNA described above strongly support the in vivo reality of some form of non-chromatin nuclear scaffold/matrix
Summary
Significant strides have been made in recent years to elucidate the effectors and processes both upstream and downstream of XIST during X chromosome inactivation (XCI) in mammalian females. It may be widely assumed that visible condensation of the inactive X chromosome into the Barr body is due to collective histone modifications or silencing transcription of genes along the chromosome. Recent evidence suggests that formation of the Barr body and X-linked silencing occurs in different cell types and stages during development despite differing extent and distribution of underlying ‘silencing’ histone modifications [17]. Histone modifications contribute to XCI, but there is evidence which leads us to suggest that XIST RNA could act at a more direct level to influence architectural proteins (figure 1b), as discussed in part elsewhere [18,19,20]. We explore the possibility that rather than an exception in RNA biology, XIST serves as a window into a general property of RNAs to influence the architecture of chromosomes
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