Effects of sex chromosome constitution on global gene expression

性染色体构成对整体基因表达的影响

• 批准号: 10267656
• 负责人: Adrianna K San Roman
• 金额: $ 4.06万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267656
• 关键词: Affect; Basic Science; Candidate Disease Gene; Cell Culture Techniques; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Constitution; DNA; DNA-Directed RNA Polymerase; Development; Disease; Enzymes; Epigenetic Process; Female; Fibroblasts; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Health; Histones; Human; Human Development; Individual; Klinefelter' s Syndrome; Link; Longevity; Lymphocyte; Modeling; Modification; Pathogenesis; Phenotype; Play; Ploidies; Prevalence; Property; Proteins; Regulator Genes; Role; Series; Severities; Sex Bias; Sex Chromosomes; Sex Differences; Testing; Tissues; Treatment outcome; Trisomy X syndrome; Turner' s Syndrome; United States National Institutes of Health; Variant; Work; X Chromosome; X Inactivation; XY females; XYY Karyotype; Y Chromosome; cell type; clinical center; clinically relevant; differential expression; dosage; epidemiology study; epigenome; genome-wide; histone modification; human female; human male; insight; male; programs; sex; sexual dimorphism; symptom treatment; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Males and females have striking differences in development, health and disease, but the underlying mechanisms remain poorly understood. At the genetic level, different sex chromosome constitutions, XX in females and XY in males, result in differential expression of sex chromosome genes. Autosomal genes are also differentially expressed between the sexes, but, since autosomal DNA content does not vary by sex, this difference is evidently due to epigenetics. Interestingly, sex chromosome genes encode transcription factors and chromatin modifiers, which may have different expression levels and/or activities in males and females. Thus, I hypothesize that the actions of epigenetic and transcriptional regulators encoded by the X and Y chromosomes create sexually dimorphic expression across the genome. In Aim 1, I will ascertain whether epigenetic and transcriptional programs depend on sex chromosome dosage using cells from males and females varying in their sex chromosome complement (XO, XX, XY, XXY, XYY, and XXX). In Aim 2, I will assess activities of candidate regulatory genes on the sex chromosomes in males and females, and individually manipulate them to investigate their functional roles in epigenetic and transcriptional sex differences. This work will increase our mechanistic understanding of differences between the sexes, and motivate future research on sex-biased diseases.

项目摘要/摘要 男性和女性在发展，健康和疾病方面有明显的差异，但基础 机制仍然很少理解。在遗传水平上，不同的性染色体构成， 女性中的XX和男性的XY，导致性染色体基因的差异表达。 常染色体基因在性别之间也有差异表达，但是，由于常染色体DNA 内容不会因性别而异，因此这种差异显然是由于表观遗传学。有趣的是，性 染色体基因编码转录因子和染色质修饰剂，可能具有不同的 男性和女性的表达水平和/或活动。因此，我假设 由X和Y染色体编码的表观遗传和转录调节剂会产生性别 整个基因组的双态表达。在AIM 1中，我将确定是否表观遗传和 转录程序取决于使用男性和女性细胞的性染色体剂量 他们的性染色体补体（XO，XX，XY，XXY，XYY和XXX）有所不同。在AIM 2中，我会 评估候选监管基因对男性和女性性别染色体的活动，以及 单独操纵它们以研究其在表观遗传和转录性别中的功能作用 差异。这项工作将增加我们对性别差异的机械理解， 并激发未来对性偏见疾病的研究。

项目成果

Genetic counseling for women with 45,X/46,XX mosaicism: Towards more personalized management.

为 45,X/46,XX 嵌合体女性提供遗传咨询：走向更个性化的管理。

• DOI: 10.1016/j.ejmg.2021.104140
• 发表时间: 2021
• 期刊: European journal of medical genetics
• 影响因子: 1.9
• 作者: Snyder,EmmaA;SanRoman,AdriannaK;Piña-Aguilar,RaulE;Steeves,MarcieA;McNamara,ErinA;Souter,Irene;Hayes,FrancesJ;Levitsky,LynneL;Lin,AngelaE
• 通讯作者: Lin,AngelaE

The human inactive X chromosome modulates expression of the active X chromosome.

• DOI: 10.1016/j.xgen.2023.100259
• 发表时间: 2023-02-08
• 期刊: Cell genomics
• 作者: San Roman AK;Godfrey AK;Skaletsky H;Bellott DW;Groff AF;Harris HL;Blanton LV;Hughes JF;Brown L;Phou S;Buscetta A;Kruszka P;Banks N;Dutra A;Pak E;Lasutschinkow PC;Keen C;Davis SM;Tartaglia NR;Samango-Sprouse C;Muenke M;Page DC
• 通讯作者: Page DC

"Donating our bodies to science": A discussion about autopsy and organ donation in Turner syndrome.

“将我们的身体捐赠给科学”：关于特纳综合征尸检和器官捐赠的讨论。

• DOI: 10.1002/ajmg.c.31671
• 发表时间: 2019
• 期刊: American journal of medical genetics. Part C, Seminars in medical genetics
• 作者: Prakash,SiddharthK;SanRoman,AdriannaK;Crenshaw,Melissa;Flink,Barbara;Earle,Kimberly;Los,Evan;Bonnard,Åsa;Lin,AngelaE
• 通讯作者: Lin,AngelaE