Chromatin StructureDevelopmental Biology & Stem Cells

The Y chromosome has genome-wide influences over chromatin structure and gene regulation

The Y chromosome has genome-wide influences over chromatin structure and gene regulationIn mammals, the Y chromosome is responsible for determining the male sex by initiating the development of male-specific gonad tissues. Hormones, produced and secreted by the sex organs, are vital for initiating and maintaining sexual dimorphisms. However, differences seen between the sexes are not solely derived from hormones. In fact, sexual differentiation begins in early embryonic development – before hormones have even begun to be produced. Some genes on both autosomal and sex chromosomes are differentially expressed between the sexes, prior to gonad differentiation.2,5  In embryonic stem cells, a XX sex compliment is associated with decreased global DNA methylation compared to XY and X0 cells.15  Sex compliments (XX vs XY) also influences the imprinting of autosomal alleles.6

Until recently the majority of the Y chromosome was considered to a genetic wasteland – composed primarily of “junk DNA”. Of the 80 or so genes found on the Y chromosome, only the “sex-determining region of Y” (SRY) gene is responsible for deciding the male sex. More recent studies however, have found evidence that the Y chromosome is involved in more than simply sex determination and spermatogenesis. The non-sex determining regions of the Y chromosome have been shown to influence cerebral asymmetry, stature, tooth size, handedness, testoblastoma, and other male specific cancers.3,4,7,9,10,11,14

Scattered throughout the Y chromosome are short, tandem repeats of sequences, predominantly found clustered in coding regions of the Y chromosome and near the centromere.13 These tandem repeats are able to associate with many different regions of the genome and influence cell processes such as genome organization, replication, and transcription. The unique epigenetic marks found on these tandem repeats can regulate expression of distant loci by acting as regulatory elements and by recruiting transcription factors and transcriptional machinery to genes not necessarily located on the Y chromosome.12 Thus, the Y chromosome has the ability to set the functional state of the rest of the genome.

More evidence of the Y chromosome’s ability to regulate genome-wide processes comes from analysis of genes shared between both sex chromosomes. X-Y shared genes are enriched in regions which are annotated as being involved with nucleic acid binding, transcription, and translation, implying that both X and Y chromosomes are able to influence expression of target genes scattered throughout the genome.1 The genes shared between the X and Y chromosomes are also able to escape normal X-inactivation in females, suggesting that the full expression of both parent alleles is vital to the well-being of both sexes.1

There is a growing amount of evidence showing crosstalk between the autosomal and sex chromosomes. In mammals, the presence of a Y chromosome results in a male phenotype. In mice, the expression of the sex-determining SRY gene is modulated by an autosomal histone demthylase gene (Kdm3a). When both copies of Kdm3a are deleted, male embryos can exhibit partial or full male-to-female reversal, and these XY mice can develop normally into fertile female adults.8 In drosophila, an XX geneotype results in a female phenotype, and XY in male. Unlike mammals however, an XXY drosophila geneotype also results in a female phenotype. These XXY organisms do not actively express the male genes found along the Y chromosome, yet they still show genome-wide transacting effects of Y-link variation on expression of autosomal genes.

Other than determining sex, the Y chromosome has, until recently, been believed to be composed of primarily junk DNA. Recent advancements in sequencing technology have allowed for new studies that show that the Y chromosome has the potential to regulate autosomal genes, and in turn, autosomal genes are able to regulate sexual differentiation. Thus, there may be much more to being male or female than has previously been believed.

 

  1. Bellott DW, Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Cho TJ, Koutseva N, Zaghlul S, Graves T, Rock S, Kremitzki C, Fulton RS, Dugan S, Ding Y, Morton D, Khan Z, Lewis L, Buhay C, Wang Q, Watt J, Holder M, Lee S, Nazareth L, Rozen S, Muzny DM, Warren WC, Gibbs RA, Wilson RK, & Page DC (2014). Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature, 508 (7497), 494-9 PMID: 24759411
  2. Bermejo-Alvarez P, Rizos D, Lonergan P, & Gutierrez-Adan A (2011). Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes. Reproduction (Cambridge, England), 141 (6), 801-8 PMID: 21411694
  3. Crow TJ (2002). Handedness, language lateralisation and anatomical asymmetry: relevance of protocadherin XY to hominid speciation and the aetiology of psychosis. Point of view. The British journal of psychiatry : the journal of mental science, 181, 295-7 PMID: 12356655
  4. Delbridge ML, Longepied G, Depetris D, Mattei MG, Disteche CM, Marshall Graves JA, & Mitchell MJ (2004). TSPY, the candidate gonadoblastoma gene on the human Y chromosome, has a widely expressed homologue on the X – implications for Y chromosome evolution. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 12 (4), 345-56 PMID: 15241014
  5. Dewing P, Shi T, Horvath S, & Vilain E (2003). Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain research. Molecular brain research, 118 (1-2), 82-90 PMID: 14559357
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  7. Jobling MA, & Tyler-Smith C (2003). The human Y chromosome: an evolutionary marker comes of age. Nature reviews. Genetics, 4 (8), 598-612 PMID: 12897772
  8. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, & Tachibana M (2013). Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science (New York, N.Y.), 341 (6150), 1106-9 PMID: 24009392
  9. Lahn BT, & Page DC (1997). Functional coherence of the human Y chromosome. Science (New York, N.Y.), 278 (5338), 675-80 PMID: 9381176
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  11. Oram SW, Liu XX, Lee TL, Chan WY, & Lau YF (2006). TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells. BMC cancer, 6 PMID: 16762081
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Eliza B.

Eliza B.

Eliza was born and raised in Southern California and is currently pursuing her graduate degree in Neuroscience. When she’s not in the lab or class you can find her zipping around town on her motorcycle, rock climbing, or baking cookies.