Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model

Qing Yang; Qiang Cao; Yue Yu; Xianxin Lai; Jiahao Feng; Xinjie Li; Yinan Jiang; Yazhou Sun; Zhong-Wei Zhou; Xin Li

doi:10.1016/j.jgg.2023.10.006

Volume 51 Issue 4

Apr. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(4): 419-432

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Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model

doi: 10.1016/j.jgg.2023.10.006

a. School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China;
b. Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China;
c. Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China;
d. Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China

Funds:

We are grateful to Dr. Wen Zong for her contribution to the sample collection of Mcph1-del mice. This work was supported by the National Natural Science Foundation of China (81872299 to X.L. and 3217070538 to W.Z.Z.), Shenzhen Science and Technology Program (JCYJ20190807160011600 and JCYJ20210324124808023 to X.L.

JCYJ20200109142446804, JCYJ20220530145807018, ZDSYS20220606100803007, and JCYJ20190807154407467 to W.Z. Z.), Guangdong Provincial Key Laboratory of Digestive Cancer Research (2021B1212040006 to X.L.), and China Postdoctoral Science Foundation (2020M683073 to Y.Z.S.).

Received Date: 2023-07-17
Accepted Date: 2023-10-25
Rev Recd Date: 2023-10-24

Available Online: 2025-06-06

Publish Date: 2023-11-01

Abstract

Abstract

The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system. DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5′-hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program, which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.
- Microcephaly,
- Epigenetic modification,
- Tet1,
- Cerebral cortex development,
- DNA hydroxymethylome,
- Transcriptome

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References(56)

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