Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors
Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors
批准号:
10222655
负责人:
Ramesh A Shivdasani
金额:
$38.22万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-01 至 2023-02-28
关键词:
Active SitesAddressAdultAffectBarrett EsophagusBiochemicalCDX2 geneCellsChromatinColorectal CancerData SetDependenceDepositionDevelopmentDigestive System DisordersDiseaseDistantEctopic ExpressionElementsEmbryoEndodermEnhancersEnterocytesEpithelialFunctional disorderFundingGastrointestinal tract structureGene ExpressionGene Expression RegulationGenesGeneticGenomicsGoalsGrowthHNF4A geneHealthHistonesHormonalImmunoprecipitationInflammatory Bowel DiseasesIntestinal CancerIntestinesKnowledgeLifeMapsMetabolicMolecularMusNucleic Acid Regulatory SequencesOrganProcessProliferatingPropertyProteinsRegulationRegulator GenesRepressionRoleSiteSpecificityStomachStructureTechnologyTestingTimeTissuesTransactivationTranscriptVillusWild Type Mousecrypt cellepigenomeexperimental studyfetalgastrointestinal epitheliumgene complementationgene repressionhepatic nuclear factor 1improvedin vivoinnovationintestinal cryptintestinal epitheliumintestinal villimRNA Expressionnovelnovel therapeuticsprogenitorrecruitspatiotemporaltranscription factortranscription factor CDX2
中文摘要
项目描述
常见的消化道疾病,如炎症性肠病、结直肠癌和
Barrett食管反映了严重的上皮功能障碍和基因失调。改进的治疗
需要更好地理解的基础上,为特定的基因控制。某些转录因子
(TFs)- CDX 2、HNF 4和HNF 1-作用于定义肠道上皮身份的基因的远端增强子
和功能,但增强子组装,特异性和活性的机制还没有很好地理解。也不
是否知道肠内胚层中的染色质和TF动力学是如何允许独特的消化系统的出现的?
上皮细胞该提案解决了小鼠体内肠细胞中的一些基本问题。
在成千上万的控制肠道基因的顺式元件中,我们发现了一类新的组织特异性元件。
需要CDX 2从大基因组中排除抑制性组蛋白标记H3 K27 me 3的增强子
H3 K27 me 3先前未涉及成体组织中的远端增强子。这些发现
归因于CDX 2在“抗抑制”1A型增强子中的一种新的、意想不到的功能,
Cdx 2-/-绒毛细胞中的定量脆弱基因。具体目标1涉及各项要求,
这些新的增强剂的机制。我们提出了遗传和生化实验来测试两个
中心假设:(a)约500个关键的肠道基因座特别容易受到抑制,
H3 K27 me 3的广泛局部沉积,和(B)CDX 2募集特异性H3 K27脱甲基酶
KDM 6A/B来对抗这种基因座效应。我们将使用缺乏甲基化H3 K27的Eed-/-肠,
确定这一特征是否是因果压抑,并试图拯救基因中最受干扰的基因。
Cdx 2-/-肠。因为1A型增强子在H3 K27 me 3水平上显示出很大的差异,
肠上皮细胞祖细胞在肠隐窝和终末成熟肠上皮细胞沿着绒毛,我们提出,
这些研究旨在验证这一抑制性标记限制了肠上皮细胞基因的高表达这一假设,
不断复制的隐窝细胞具体目标2考虑了肠道发育的起源和决定因素,
增强子,并询问为什么某些基因组结构域获得组织特异性H3 K27 me 3。这一目标建立在
我们发现,所有消化上皮的新生增强子最初在整个早期都是可获得的,
内胚层和组织特异性位点随后在每个器官中增强,而不适当的增强剂
关闭我们将检验这一假设,即成人肠道中依赖于1A型增强子的区域
是用于发育的增强剂的残留。我们还将检验以下假设:(a)
除非局部TF增强开放的内胚层染色质,否则增强子在头-尾波中关闭,
和(B)染色质在任何时间的状态决定发育中的肠如何对缺乏
CDX2。因此,该提案采用创新的最先进方法来追求令人兴奋的发现,
解决体内肠道基因调控的基本问题。
英文摘要
Project Description
Common disorders of the digestive tract, such as Inflammatory Bowel Disease, colorectal cancer and
Barrett's esophagus reflect profound epithelial dysfunction and gene dysregulation. Improved treatments
require better understanding of the basis for intestine-specific gene control. Certain transcription factors
(TFs) – CDX2, HNF4 and HNF1 – act at the distant enhancers of genes that define gut epithelial identity
and function, but mechanisms of enhancer assembly, specificity, and activity are not well understood. Nor
is it known how chromatin and TF dynamics in gut endoderm allow the emergence of distinctive digestive
epithelia. This proposal addresses some of these fundamental questions in mouse intestinal cells in vivo.
Among thousands of cis-elements that control intestinal genes, we identify a new class of tissue-specific
enhancers that require CDX2 to exclude the repressive histone mark H3K27me3 from large genomic
domains; H3K27me3 was not previously implicated at distant enhancers in adult tissues. These findings
ascribe a novel, unexpected function for CDX2 at `anti-repressive' Type 1A enhancers that control the most
quantitatively vulnerable genes in Cdx2-/- villus cells. Specific Aim 1 addresses the requirements and
mechanisms of these novel enhancers. We propose genetic and biochemical experiments to test two
central hypotheses: (a) that ~500 key intestinal loci are particularly susceptible to repression by virtue of
extensive local deposition of H3K27me3, and (b) that CDX2 recruits the specific H3K27 demethylases
KDM6A/B to oppose that locus-wide effect. We will use Eed-/- intestines, which lack methylated H3K27, to
determine whether this feature is causally repressive and to attempt rescue of the genes most perturbed in
Cdx2-/- intestines. Because Type 1A enhancers show a large difference in H3K27me3 levels between
enterocyte progenitors in intestinal crypts and terminally mature enterocytes along the villi, we propose
studies to test the hypothesis that this repressive mark limits high expression of enterocyte genes in
replicating crypt cells. Specific Aim 2 considers the developmental origins and determinants of intestinal
enhancers and asks why certain genomic domains acquire tissue-specific H3K27me3. This Aim builds on
our discovery that nascent enhancers for all digestive epithelia are initially accessible throughout the early
endoderm and that tissue-specific sites later strengthen in each organ while inappropriate enhancers are
shut down. We will test the hypothesis that regions dependent on Type 1A enhancers in the adult intestine
are the vestiges of enhancers that were used in development. We will also test the hypotheses that: (a)
unless regional TFs reinforce open endodermal chromatin, enhancers shut down in a rostral-caudal wave,
and (b) the state of chromatin at any time determines how the developing intestine responds to absence of
CDX2. This proposal thus applies innovative state-of-the-art approaches to pursue exciting discoveries and
address fundamental questions about intestinal gene regulation in vivo.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Development and vascularity of intestinal mesenchyme
-
批准号:10735493
-
项目类别:
-
资助金额:$44.81万
-
财政年份:2019
-
负责人:Ramesh A Shivdasani
-
依托单位:
Cellular and molecular characterization of the digestive tract sub-epithelium
-
批准号:9764595
-
项目类别:
-
资助金额:$37.31万
-
财政年份:2019
-
负责人:Ramesh A Shivdasani
-
依托单位:
Cellular and molecular characterization of the digestive tract sub-epithelium
-
批准号:10381661
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2019
-
负责人:Ramesh A Shivdasani
-
依托单位:
Chromatin and transcriptional control of LGR5+ crypt base stem cells
-
批准号:9135746
-
项目类别:
-
资助金额:$5.49万
-
财政年份:2014
-
负责人:Ramesh A Shivdasani
-
依托单位:
Anatomic and functional characterization of the intestinal crypt-villus niche
-
批准号:10237318
-
项目类别:
-
资助金额:$41.97万
-
财政年份:2014
-
负责人:Ramesh A Shivdasani
-
依托单位:
Anatomic and functional characterization of the intestinal crypt-villus niche
-
批准号:10469333
-
项目类别:
-
资助金额:$41.97万
-
财政年份:2014
-
负责人:Ramesh A Shivdasani
-
依托单位:
Chromatin and transcriptional control of LGR5+ crypt base stem cells
-
批准号:9333357
-
项目类别:
-
资助金额:$36.74万
-
财政年份:2014
-
负责人:Ramesh A Shivdasani
-
依托单位:
Chromatin and transcriptional control of LGR5+ crypt base stem cells
-
批准号:9130871
-
项目类别:
-
资助金额:$36.74万
-
财政年份:2014
-
负责人:Ramesh A Shivdasani
-
依托单位:
Transcriptional control and enhancer recruitment in mouse and human intestinal secretory differentiation
-
批准号:10584678
-
项目类别:
-
资助金额:$37.26万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Analysis of intestinal genes regulated by the transcription factor CDX2
-
批准号:7918716
-
项目类别:
-
资助金额:$42.62万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Analysis of intestinal genes regulated by the transcription factor CDX2
-
批准号:8102916
-
项目类别:
-
资助金额:$35.7万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors
-
批准号:9403492
-
项目类别:
-
资助金额:$38.22万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Analysis of intestinal genes regulated by the transcription factor CDX2
-
批准号:8322166
-
项目类别:
-
资助金额:$35.7万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors
-
批准号:9978814
-
项目类别:
-
资助金额:$38.22万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Analysis of intestinal genes regulated by the transcription factor CDX2
-
批准号:8717640
-
项目类别:
-
资助金额:$35.7万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Analysis of intestinal genes regulated by the transcription factor CDX2
-
批准号:8538942
-
项目类别:
-
资助金额:$34.45万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors
-
批准号:9537499
-
项目类别:
-
资助金额:$38.22万
-
财政年份:2010
-
负责人:Ramesh A Shivdasani
-
依托单位:
Hedgehog signaling in early development of the gastrointestinal tract
-
批准号:7590197
-
项目类别:
-
资助金额:$40.89万
-
财政年份:2009
-
负责人:Ramesh A Shivdasani
-
依托单位:
Hedgehog signaling in early development of the gastrointestinal tract
-
批准号:8314081
-
项目类别:
-
资助金额:$36.92万
-
财政年份:2009
-
负责人:Ramesh A Shivdasani
-
依托单位:
Signaling in digestive epithelial development and homeostasis
-
批准号:9128613
-
项目类别:
-
资助金额:$36.11万
-
财政年份:2009
-
负责人:Ramesh A Shivdasani
-
依托单位:
海外基金