Targeting acetylated histone H4 by MLL4
MLL4 靶向乙酰化组蛋白 H4
基本信息
- 批准号:10202000
- 负责人:
- 金额:$ 52.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAcetyltransferaseAffinityAgingAlzheimer&aposs DiseaseBindingBinding ProteinsBiologicalBiological AssayCalorimetryCell physiologyChromatinComplexCrystallizationDNA RepairDiseaseEpigenetic ProcessEtiologyFingersFluorescenceGene ExpressionGenetic TranscriptionGenomicsHistone AcetylationHistone H3Histone H4HistonesHumanIn VitroLengthLightLinkLysineMalignant NeoplasmsMeasuresMediatingMethyltransferaseModelingModificationMolecularMutagenesisNeurodegenerative DisordersPHD FingerPathogenicityPeptidesPhysiologicalPlantsPlayPost-Translational Protein ProcessingProtein AcetylationReaderReadingRoleSignal TransductionSiteSpecificityStructureTailTherapeuticTitrationsTranscriptional ActivationWestern BlottingWritingage relatedaging brainchromatin immunoprecipitationdesigngene interactionhistone methyltransferasehistone modificationhomeodomainhuman diseasein vivoinsightloss of functionmutantnovelpreventscreening
项目摘要
Project Summary
Epigenetic mechanisms play a pivotal role in aging and are found disregulated in age-related
disorders, including neurodegenerative diseases and cancer. The major indicator of alterations
occurred in chromatin during aging is acetylation of lysine 16 of histone H4 (H4K16ac), a
modification that is redistributed and raised in the healthy aged brain but is considerably lost in
Alzheimer’s disease. On the molecular level, H4K16ac is involved in a wide array of fundamental
cellular processes, including higher-order chromatin decompaction and folding, DNA damage
repair, and gene expression. Despite the high importance of H4K16ac, very little is known about
protein ligands that bind this mark. Our recent studies identified the plant homeodomain finger 6
of the histone methyltransferase MLL4 (MLL4PHD6) as a selective effector (or reader) of H4K16ac.
The molecular mechanism underlying the recognition of H4K16ac by MLL4 is unknown and will
be elucidated in the proposed studies. We hypothesize that the selective targeting of H4K16ac
by MLL4 at specific genomic sites is necessary for transcriptional activation of MLL4 target genes
and that this interaction provides a novel functional link between MLL4 that methylates lysine 4 of
histone H3 (H3K4) and the acetyltransferase MOF that produces H4K16ac. We seek to define
the molecular basis and functional significance of the previously uncharacterized crosstalk
between vital histone marks. These studies are fundamental to our understanding of physiological
activities associated with ‘writing and reading’ H4K16ac and are also essential to better
understand the etiology of human age-related illnesses, including AD and other
neurodegenerative disorders.
项目摘要
表观遗传机制在衰老中起着关键作用,并且发现与年龄相关的
疾病,包括神经退行性疾病和癌症。变化的主要指标
在衰老过程中,组蛋白H4的赖氨酸16(H4K16ac)发生乙酰化,
在健康的老年大脑中重新分配和提高,但在健康的老年大脑中大量丢失。
老年痴呆症在分子水平上,H4K16ac参与了广泛的基本生物学过程。
细胞过程,包括高阶染色质解压缩和折叠,DNA损伤
修复和基因表达。尽管H4K16ac的重要性很高,但人们对它知之甚少。
结合该标记的蛋白质配体。我们最近的研究确定了植物同源结构域指6
组蛋白甲基转移酶MLL4(MLL4PHD6)作为H4K16ac的选择性效应子(或阅读器)。
MLL4识别H4K16ac的分子机制尚不清楚,
在拟议的研究中予以阐明。我们假设H4 K16 ac的选择性靶向
在特定基因组位点被MLL4激活是MLL4靶基因转录激活所必需的
并且这种相互作用在MLL4之间提供了一种新的功能性连接,MLL4甲基化
组蛋白H3(H3K4)和产生H4K16ac的乙酰转移酶MOF。我们试图定义
先前未表征的串扰的分子基础和功能意义
重要的组蛋白标记之间。这些研究对于我们理解生理学
与“写和阅读”相关的活动H4K16 ac,也是更好地
了解人类年龄相关疾病的病因,包括AD和其他
神经退行性疾病
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
TATIANA G KUTATELADZE其他文献
TATIANA G KUTATELADZE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('TATIANA G KUTATELADZE', 18)}}的其他基金
相似海外基金
Dissecting out differential molecular phenotypes across Lysine(K) AcetylTransferase mutations in mouse development
剖析小鼠发育过程中赖氨酸(K)乙酰转移酶突变的差异分子表型
- 批准号:
10727966 - 财政年份:2023
- 资助金额:
$ 52.75万 - 项目类别:
Targeting lysine acetyltransferase MOF/KAT8 in lung cancer
靶向赖氨酸乙酰转移酶 MOF/KAT8 在肺癌中的作用
- 批准号:
10601761 - 财政年份:2023
- 资助金额:
$ 52.75万 - 项目类别:
Defining the cell-type specific role of histone acetyltransferase KAT2a in nucleus accumbens D1 medium spiny neurons as a driver of cocaine use disorder
定义组蛋白乙酰转移酶 KAT2a 在伏隔核 D1 中型多棘神经元中作为可卡因使用障碍驱动因素的细胞类型特异性作用
- 批准号:
10679238 - 财政年份:2023
- 资助金额:
$ 52.75万 - 项目类别:
Roles of lysine acetyltransferase 6 complexes in cerebral development and neurodevelopmental disorders
赖氨酸乙酰转移酶 6 复合物在大脑发育和神经发育障碍中的作用
- 批准号:
479754 - 财政年份:2023
- 资助金额:
$ 52.75万 - 项目类别:
Operating Grants
Examination of the Histone Acetyltransferase CBP in the Remodelling of Thermogenic Adipose Tissues
组蛋白乙酰转移酶 CBP 在生热脂肪组织重塑中的检测
- 批准号:
486467 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Studentship Programs
Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
- 批准号:
10344246 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Discovery Grants Program - Individual
Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
- 批准号:
10627744 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Structural and functional studies of histone acetyltransferase complexes
组蛋白乙酰转移酶复合物的结构和功能研究
- 批准号:
RGPIN-2018-03951 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Discovery Grants Program - Individual
Characterizing the role of the NuA3 histone acetyltransferase complex during transcription
表征 NuA3 组蛋白乙酰转移酶复合物在转录过程中的作用
- 批准号:
557615-2021 - 财政年份:2022
- 资助金额:
$ 52.75万 - 项目类别:
Postdoctoral Fellowships