Chromatin Organization Regulates Osteogenesis
染色质组织调节成骨
基本信息
- 批准号:10316201
- 负责人:
- 金额:$ 50.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-06 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcuteAffectAgingAlkaline PhosphataseBindingBiological AssayBone DevelopmentBone RegenerationBone SurfaceBone TissueCCCTC-binding factorCRISPR/Cas technologyCell LineageCellsChromatinChromatin StructureChromosomesClustered Regularly Interspaced Short Palindromic RepeatsCompetenceComplementComplexControl GroupsData SetDevelopmentEnhancersEpigenetic ProcessFemaleFutureGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGenomeGenomic SegmentGenomicsHi-CHigher Order Chromatin StructureHistologyImpairmentImplantInjectionsKnowledgeLinkMature BoneMediatingMesenchymal Stem CellsMicroRNAsModelingModificationMusOsteoblastsOsteogenesisOutcomePhenotypePublishingRegulatory ElementResearchResolutionRoleSelection CriteriaSupporting CellTestingTherapeuticTimeTissuesTranscriptional RegulationTransplantationUndifferentiatedbasebonebone losschromosomal locationclinically relevantcohortdifferential expressionfunctional genomicsgene networkhistone modificationin vivoin vivo evaluationmalemouse modelnovelosteoblast differentiationosteogenicpreventive interventionprogramsprotein complexskeletal disorderstem cellssubcutaneoustranscription factortranscriptome sequencingtranslational applicationstreatment strategy
项目摘要
SUMMARY
This new R01 builds on discoveries during the R37 period (2008-2018) that established epigenetic mechanisms
(miRNAs, histone modifications) regulating osteoblast differentiation. We characterized for the first time a
“signature” of specific histone modifications that are associated with dynamic changes in gene expression during
the temporal progression of osteogenesis. These histone modifications also predicted “enhancers”, which are
critical cis-regulatory elements that contribute to local gene expression. We now propose to examine the recently
recognized “super enhancer” domains (SEDs) that include regulatory elements for multiple transcription factors
that have emerged as key regulators of cell phenotypes. SEDs function in chromatin organization via long range
intra- and inter-chromosomal interactions that coordinate control of gene cohorts responsible for lineage
specification and distinct cell identity. Our preliminary studies have identified a subset of SEDs that we now
propose are putative “bone-essential super-enhancers” and candidates for the important decision stage of
commitment to osteogenesis from MSCs. We hypothesize that super-enhancer domains are differentially
activated from the undifferentiated MSC to the osteoblast commitment stage, and function to establish the
osteogenic phenotype by coordinately regulating gene networks and contributing to higher order chromatin
organization that supports cell identity. Our studies will in: Aim1- analyze the functional effects of prioritized SEDs
we have identified related to osteoblastogenesis and mature bone activities through directed inhibition and
activation of SEDs using CRISPR/Cas9 in MSCs; Aim 2- determine the chromosomal domains that interact
with SEDs to control multiple genes and networks that commit MSCs to the osteoblast phenotype through
chromatin organization; and Aim 3- demonstrate in mouse models that using CRISPR activated SEDs in MSCs
will stimulate bone formation.
Impact: These studies pioneer a new level of gene regulation for MSC lineage commitment to osteogenesis,
based on an emerging understanding of SED functions in other tissues but have been minimally studied in bone.
By characterizing SED mechanisms related to chromatin organization and stabilization in MSCs, we will discover
novel mechanisms of multi-dimensional coordinate control of transcriptional hubs and protein complexes within
an SED that is responsible for establishing commitment to the osteoblast phenotype. Importantly, knowledge of
the chromatin organization that stabilizes the osteogenic phenotype impacts on future novel treatment strategies
for skeletal disorders.
总结
这种新的R 01建立在R37期间(2008-2018)的发现基础上,这些发现建立了表观遗传机制
(miRNAs,组蛋白修饰)调控成骨细胞分化。我们首次描述了
特定组蛋白修饰的“签名”,其与在基因表达过程中的动态变化相关。
骨生成的时间进程这些组蛋白修饰也预测了“增强子”,
关键的顺式调控元件,有助于局部基因表达。我们现在建议研究最近
公认的“超级增强子”结构域(SED),包括多种转录因子的调控元件
已经成为细胞表型的关键调节因子。SEDs通过长距离作用于染色质组织
染色体内和染色体间相互作用,协调控制负责谱系的基因组
规范和独特的小区标识。我们的初步研究已经确定了一个子集的SED,
建议是公认的“骨必需的超级增强剂”和候选人的重要决定阶段,
致力于从MSC成骨。我们假设超级增强子结构域是不同的,
从未分化的MSC激活到成骨细胞定型阶段,并发挥作用,
成骨表型通过协调调节基因网络和促进更高级的染色质
支持细胞识别的组织。我们的研究将在:目的1-分析优先的SED的功能效果
我们已经通过定向抑制确定了与成骨细胞生成和成熟骨活性相关的,
在MSC中使用CRISPR/Cas9激活SED;目的2-确定相互作用的染色体域
与SED控制多个基因和网络,使MSC成为成骨细胞表型,
目的3-在小鼠模型中证明使用CRISPR激活MSC中的SED
会刺激骨骼形成
影响:这些研究开创了MSC谱系致力于成骨的基因调控的新水平,
基于对其他组织中SED功能的新认识,但在骨中的研究很少。
通过表征与MSC中染色质组织和稳定相关的SED机制,我们将发现
转录枢纽和蛋白质复合物的多维协调控制的新机制,
一种负责建立成骨细胞表型定型的SED。重要的是,
稳定成骨表型的染色质组织对未来新治疗策略的影响
治疗骨骼疾病
项目成果
期刊论文数量(0)
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Jane B. Lian其他文献
Networks and hubs for the transcriptional control of osteoblastogenesis
- DOI:
10.1007/s11154-006-9001-5 - 发表时间:
2006-06-01 - 期刊:
- 影响因子:8.000
- 作者:
Jane B. Lian;Gary S. Stein;Amjad Javed;Andre J. van Wijnen;Janet L. Stein;Martin Montecino;Mohammad Q. Hassan;Tripti Gaur;Christopher J. Lengner;Daniel W. Young - 通讯作者:
Daniel W. Young
Gamma-carboxyglutamate excretion and calcinosis in juvenile dermatomyositis.
幼年皮肌炎中的γ-羧基谷氨酸排泄和钙质沉着。
- DOI:
10.1002/art.1780250910 - 发表时间:
1982 - 期刊:
- 影响因子:0
- 作者:
Jane B. Lian;Jane B. Lian;Lauren M. Pachman;C. Gundberg;Raymond E. H. Partridge;M. Maryjowski - 通讯作者:
M. Maryjowski
LB-036 - Cbfβ prevents articular cartilage degeneration
- DOI:
10.1016/j.joca.2024.03.038 - 发表时间:
2024-06-01 - 期刊:
- 影响因子:
- 作者:
Xiangguo Che;Xian Jin;Dong-Kyo Lee;Hee-June Kim;Hee-Soo Kyung;Hyun-Ju Kim;Jane B. Lian;Janet L. Stein;Gary S. Stein;Je-Yong Choi - 通讯作者:
Je-Yong Choi
Mitotic bookmarking of genes: a novel dimension to epigenetic control
基因的有丝分裂书签:表观遗传控制的一个新维度
- DOI:
10.1038/nrg2827 - 发表时间:
2010-07-13 - 期刊:
- 影响因子:52.000
- 作者:
Sayyed K. Zaidi;Daniel W. Young;Martin A. Montecino;Jane B. Lian;Andre J. van Wijnen;Janet L. Stein;Gary S. Stein - 通讯作者:
Gary S. Stein
Nuclear microenvironments in biological control and cancer
生物防治和癌症中的核微环境
- DOI:
10.1038/nrc2149 - 发表时间:
2007-06-01 - 期刊:
- 影响因子:66.800
- 作者:
Sayyed K. Zaidi;Daniel W. Young;Amjad Javed;Jitesh Pratap;Martin Montecino;Andre van Wijnen;Jane B. Lian;Janet L. Stein;Gary S. Stein - 通讯作者:
Gary S. Stein
Jane B. Lian的其他文献
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{{ truncateString('Jane B. Lian', 18)}}的其他基金
Project 3: MANCR Mediates Epigenetic Mechanisms for Survival of Advanced Breast Cancer
项目 3:MANCR 介导晚期乳腺癌生存的表观遗传机制
- 批准号:
10380073 - 财政年份:2021
- 资助金额:
$ 50.13万 - 项目类别:
Project 3: MANCR Mediates Epigenetic Mechanisms for Survival of Advanced Breast Cancer
项目 3:MANCR 介导晚期乳腺癌生存的表观遗传机制
- 批准号:
10608059 - 财政年份:2021
- 资助金额:
$ 50.13万 - 项目类别:
Runx2 Organizes Transcriptional Complexes in Nuclear Microenvironments to Support
Runx2 在核微环境中组织转录复合物以支持
- 批准号:
8601049 - 财政年份:2013
- 资助金额:
$ 50.13万 - 项目类别:
Runx2 Organizes Transcriptional Complexes in Nuclear Microenvironments to Support
Runx2 在核微环境中组织转录复合物以支持
- 批准号:
8052327 - 财政年份:2011
- 资助金额:
$ 50.13万 - 项目类别:
RUNX@ Subnuclear Targeting Integrates Signaling Pathways for Bone Formation
RUNX@ 亚核靶向整合骨形成信号通路
- 批准号:
8289359 - 财政年份:2011
- 资助金额:
$ 50.13万 - 项目类别:
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