Gene Regulation From the X-Chromosome During Development and Disease

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About this Research Topic

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Background

The sex chromosomes are the genetic basis for sex determination during development, sex differences for diseases, and often sex-biased gene expression has developmental origins. Female mammals (XX) will randomly select one X for transcriptional silencing during early development using a process called X-chromosome Inactivation (XCI), which equalizes gene expression between sexes. In the mouse, XCI initiation begins with allele-specific upregulation of the long noncoding RNA Xist, which recruits heterochromatin complexes including PRC1 and PRC2 for deposition of heterochromatin marks across the X. The resulting inactive X (Xi) chromosome is coated with Xist RNA and enriched with various heterochromatin marks, histone variants, and DNA methylation, which function to maintain transcriptional silencing. The memory of allele-specific silencing is maintained with each cell division into adulthood, where the Xi retains some or all of these epigenetic modifications. The timing and mechanistic details of XCI initiation in humans, primates, and large mammals are not well understood, yet recent work suggests significant differences with mice.

In male mammals (XY), the sex chromosomes undergo meiotic sex chromosome inactivation (MSCI), an essential epigenetic process that occurs in germ cells undergoing meiosis. During MSCI, the X and Y chromosomes become condensed and transcriptionally silent, forming a compact XY body. MSCI is required for male meiosis, yet the reasons for this silencing at this developmental stage are still enigmatic.

Sex differences have been observed in a variety of diseases, including cancer, cardiovascular disease, and autoimmunity. Recent work suggests that there is abnormal gene expression of X-linked genes in these disease states, yet the mechanisms responsible for these observations are unclear.

For this Research Topic, we call for original or review papers that address the following questions:


· What are novel insights regarding mechanisms of random and imprinted XCI during female development?
· What are the similarities and differences for XCI initiation in other species besides mice?
· How do the nuclear organization and 3D chromatin architecture of the Xi change during development and disease?
· How is XCI maintained in adult cells/tissues, and examples of alterations during disease?
· How do sex differences with gene expression from the X influence development and/or disease?
· How are X-linked genes regulated during gametogenesis; how do chromatin features change?
- What are the functions of the sex chromosomes during sex determination and gametogenesis?

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