Evolution of DNA methylation in the human brain.
Evolution of DNA methylation in the human brain.
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DOI：
10.1038/s41467-021-21917-7
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发表时间：
2021-04-01
影响因子：
16.6
通讯作者：
Yi SV
中科院分区：
文献类型：
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作者：
Jeong H;Mendizabal I;Berto S;Chatterjee P;Layman T;Usui N;Toriumi K;Douglas C;Singh D;Huh I;Preuss TM;Konopka G;Yi SV
DNA甲基化是人类大脑发育、学习、记忆和疾病的关键调控机制。在这里，我们阐明了DNA甲基化的变化在最近的人类大脑进化。我们展示了DNA甲基化在细胞类型和胞嘧啶背景特异性方式下的动态进化轨迹。具体而言，非CG背景下的DNA甲基化，即CH甲基化，在人脑进化过程中在神经元基因体中增加（超甲基化），有助于基因和共表达模块的人类特异性下调。CH超甲基化的影响在早期发育和神经元亚型中特别明显。相比之下，CG背景下的DNA甲基化在人脑中显示出明显的减少（低甲基化），特别是在顺式调控区，导致下游基因的上调。我们发现，神经元和少突胶质细胞之间的差异CG甲基化起源于类人猿和卡他鼻猴的分歧之前，并窝藏精神分裂症的遗传风险的强烈信号。值得注意的是，神经元和少突胶质细胞之间的差异CG甲基化的很大一部分出现在人类谱系中，因为从黑猩猩谱系的分歧，并携带显着的精神分裂症的遗传风险。因此，最近人类大脑皮层的表观遗传进化塑造了细胞调节景观，并导致神经精神疾病的脆弱性增加。DNA甲基化在大脑发育和功能中起着重要作用。在这里，作者比较了人类，黑猩猩和猕猴神经元和少突胶质细胞的全基因组甲基化，以重建细胞类型水平上DNA甲基化的进化，包括与精神分裂症遗传相关的区域。
DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases. DNA methylation plays an important role in brain development and function. Here, the authors compare whole-genome methylation in neurons and oligodendrocytes in humans, chimpanzees and macaques to reconstruct evolution of DNA methylation at cell-type level, including in regions associated with schizophrenia heritability.
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影响因子：
14.9
作者：
Feng H;Conneely KN;Wu H
通讯作者：
Wu H
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：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
82.9
作者：
通讯作者：
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