Exploring the contribution of large tandem repeat DNA to the organization and maintenance of the inactive X chromosome
探索大串联重复 DNA 对失活 X 染色体的组织和维护的贡献
基本信息
- 批准号:9324288
- 负责人:
- 金额:$ 28.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdoptedAffectAllelesAlpha CellAppearanceArchitectureBacterial Artificial ChromosomesBehaviorCCCTC-binding factorCell CycleCell Differentiation processCell NucleusCell divisionCellsCharacteristicsChromatinChromosomal InstabilityChromosome StructuresChromosome TerritoryChromosomesComplexDNADataDevelopmentDiploidyDiseaseDisease susceptibilityElementsEpigenetic ProcessEuchromatinFailureFemaleFutureGene ExpressionGene SilencingGenesGenomeGenome engineeringGoalsHeterochromatinHumanImmunofluorescence ImmunologicInterphaseLengthLinkLocationMacacaMaintenanceMalignant Epithelial CellMalignant NeoplasmsMediatingMetaphaseModelingMolecular ConformationMusMuscular DystrophiesPathway interactionsProcessProteinsRoleSideSomatic CellTandem Repeat SequencesTestingUntranslated RNAX ChromosomeX Inactivationbasecell transformationembryonic stem cellepigenetic regulationepigenomicsexperimental studyhuman femaleinsightmaletool
项目摘要
It is well established that at interphase the inactive X chromosome (Xi) adopts a specific 3-dimensional
conformation that differs from that of the active X chromosome (Xa). Yet we know very little about how this
arrangement is achieved, nor how critical this organization is to maintaining the epigenomic changes that are
characteristic of Xi. Human Xi is arranged into at least two distinct types of facultative heterochromatin that
occupy approximately a dozen alternating multi-megabase (Mb) domains along the length of the chromosome,
that by immunofluorescence gives a striped appearance to the chromosome at metaphase. At interphase
heterochromatin of the same type coalesce resulting in Xi arranging itself into two compartments resulting in a
bi-partite appearance. Several large (40-400 kilobase) tandem repeat (TR) DNA reside at the boundary
between some of these heterochromatin bands on the X chromosome. These TRs adopt an Xi-specific
euchromatin organization that is bound by the architectural protein CCCTC-binding factor (CTCF). Despite
residing 15-60 Mb apart, the TRs make frequent Xi-specific intra-chromosomal contact. Given this behavior,
the TR elements may function as epigenetically regulated Xi-specific chromosome folding elements. Using
cutting edge genome engineering tools, the largest of these TRs (DXZ4), has been removed from Xi as the
most direct way to test this hypothesis. On the Xa and male X chromosome, DXZ4 is packaged into
constitutive heterochromatin, an arrangement that is common to other autosomal TR elements. However, in
some male carcinoma cells, DXZ4 has been found to “flip” its chromatin state to one that resembles that seen
on Xi. Furthermore, a similar phenomena has been described for several autosomal TR elements in
transformed cells as well as at one autosomal TR that is responsible for a form of muscular dystrophy when in
this configuration. The ability of large TR DNA to transition between two distinct configurations, and the fact
that one form can mediate new long-range chromatin contacts makes understanding how chromatin states are
epigenetically regulated at these sequences important. Experiments described in this proposal seek to
address, (1) how chromatin states at the TRs are regulated, with an emphasis on the potential role of
associated long noncoding RNAs (lncRNAs) that alter in expression as chromatin states change, (2) assess
the impact of DXZ4 loss on the maintenance and organization of Xi, and (3) determine if the introduction of TR
elements at different locations on the X is sufficient to establish new long-range contacts. It is anticipated that
these studies will assess the function of TR DNA on the X chromosome, as well as provide mechanistic insight
into the organization and maintenance of Xi territory and the role of lncRNAs in regulating chromatin at large
TR DNA in complex genomes.
在间期,失活的X染色体(Xi)采用特定的三维结构
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brian P. Chadwick其他文献
Macrosatellite epigenetics: the two faces of DXZ4 and D4Z4
- DOI:
10.1007/s00412-009-0233-5 - 发表时间:
2009-08-19 - 期刊:
- 影响因子:2.300
- 作者:
Brian P. Chadwick - 通讯作者:
Brian P. Chadwick
Brian P. Chadwick的其他文献
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{{ truncateString('Brian P. Chadwick', 18)}}的其他基金
Developing resources to alleviate muscle atrophy in FSHD by genome engineering
通过基因组工程开发资源缓解 FSHD 肌肉萎缩
- 批准号:
8414059 - 财政年份:2012
- 资助金额:
$ 28.58万 - 项目类别:
Developing resources to alleviate muscle atrophy in FSHD by genome engineering
通过基因组工程开发资源缓解 FSHD 肌肉萎缩
- 批准号:
8532067 - 财政年份:2012
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
7008484 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
7172232 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
6862191 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
8512916 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
7342441 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
8327212 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
7921683 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
Heterochromatin on the human inactive X chromosome
人类失活 X 染色体上的异染色质
- 批准号:
8135311 - 财政年份:2005
- 资助金额:
$ 28.58万 - 项目类别:
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