The genetic architecture of DNA replication timing in human pluripotent stem cells.
The genetic architecture of DNA replication timing in human pluripotent stem cells.
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DOI：
10.1038/s41467-021-27115-9
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发表时间：
2021-11-19
影响因子：
16.6
通讯作者：
Koren A
中科院分区：
文献类型：
--
作者：
Ding Q;Edwards MM;Wang N;Zhu X;Bracci AN;Hulke ML;Hu Y;Tong Y;Hsiao J;Charvet CJ;Ghosh S;Handsaker RE;Eggan K;Merkle FT;Gerhardt J;Egli D;Clark AG;Koren A
DNA 复制遵循严格的时空程序，与染色质结构相交叉，但其遗传基础却知之甚少。为了系统地识别复制时间的遗传调节因子，我们利用了 349 名个体的人类多能干细胞的个体间变异。我们证明人类基因组的复制程序广泛编码在 DNA 中，并识别了 1,617 个顺式作用复制时间数量性状基因座 (rtQTL)——复制起始的序列决定因素。 rtQTL 可以单独发挥作用，也可以与近端和远端调节因子组合发挥作用，并且在组蛋白 H3 赖氨酸 4、9 和 36 三甲基化以及组蛋白超乙酰化位点处富集。 H3 三甲基化标记具有单独的抑制作用，但与早期复制具有协同作用。我们将多能性相关转录因子和边界元件分别确定为复制时间的正调节因子和负调节因子。总而言之，人类复制时间是由多层机制控制的，其中数十个效应器组合工作并遵循类似于转录调控的原理。细胞如何复制 DNA 的遗传基础尚不清楚。在这里，作者鉴定了超过 1000 个控制人类复制的遗传元件，并揭示了调节复制起点活动的复杂表观遗传系统。
DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome’s replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs) – sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation. The genetic basis of how cells replicate their DNA is not well understood. Here, the authors identify >1000 genetic elements that control human replication and reveal a complex epigenetic system that regulates replication origin activities.
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影响因子：
46.9
作者：
Ernst J;Kellis M
通讯作者：
Kellis M
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
14.9
作者：
Casas-Delucchi CS;van Bemmel JG;Haase S;Herce HD;Nowak D;Meilinger D;Stear JH;Leonhardt H;Cardoso MC
通讯作者：
Cardoso MC
影响因子：
7.3
作者：
Atchison ML
通讯作者：
Atchison ML
影响因子：
7
作者：
Eberle, Michael A.;Fritzilas, Epameinondas;Bentley, David R.
通讯作者：
Bentley, David R.