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.
摘要
这一新的R01建立在R37时期(2008-2018)建立表观遗传机制的发现的基础上
(miRNAs,组蛋白修饰)调节成骨细胞分化。我们第一次描述了一个
与基因表达的动态变化相关的特异组蛋白修饰的“签名”
成骨的时间进程。这些组蛋白修饰也预示着“增强剂”,它们是
影响局部基因表达的关键顺式调控元件。我们现在建议研究一下最近的
公认的包含多种转录因子调控元件的“超级增强子”结构域(SED)
它们已经成为细胞表型的关键调节因子。SEDS通过远距离在染色质组织中发挥作用
染色体内和染色体间的相互作用,协调负责谱系的基因队列的控制
规格和独特的细胞身份。我们的初步研究已经确定了SED的子集,我们现在
被推定为“骨必需的超级增强剂”,也是重要决策阶段的候选人
致力于骨髓间充质干细胞的成骨。我们假设超级增强子域是不同的
从未分化的MSC激活到成骨细胞承诺阶段,并功能建立
协调调节基因网络和促进高阶染色质的成骨表型
支持小区身份的组织。我们的研究将在以下方面:AIM1-分析优先SED的功能效应
我们已经确定了与成骨细胞形成和成熟骨活动有关的直接抑制和
在MSCs中使用CRISPR/Cas9激活SED;目标2-确定相互作用的染色体结构域
通过SEDS控制多个基因和网络,使MSCs通过
染色质组织;以及目标3-在小鼠模型中演示使用CRISPR激活MSCs中的SED
会刺激骨骼的形成。
影响:这些研究开创了对MSC谱系承诺成骨的基因调控的新水平,
基于对SED在其他组织中的功能的新兴理解,但在骨骼中的研究很少。
通过刻画MSCs中与染色质组织和稳定相关的SED机制,我们将发现
转录中心和蛋白质复合体的多维协调控制新机制
一种SED,负责建立对成骨细胞表型的承诺。重要的是,了解
稳定成骨表型的染色质组织对未来新的治疗策略产生影响
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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