ASH2L Regulates Postnatal Neurogenesis Through Onecut2-mediated Inhibition of TGF-β Signaling Pathway

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2023 Jul 11

PMID 37433907

Authors

Ya-Jie Xu

Shang-Kun Dai

Chun-Hui Duan

Zi-Han Zhang

Pei-Pei Liu

Cong Liu

Hong-Zhen Du

Xu-Kun Lu

Shijun Hu

Lei Li

Zhao-Qian Teng

Chang-Mei Liu

Affiliations

Soon will be listed here.

Abstract

The ability of neural stem/progenitor cells (NSPCs) to proliferate and differentiate is required through different stages of neurogenesis. Disturbance in the regulation of neurogenesis causes many neurological diseases, such as intellectual disability, autism, and schizophrenia. However, the intrinsic mechanisms of this regulation in neurogenesis remain poorly understood. Here, we report that Ash2l (Absent, small or homeotic discs-like 2), one core component of a multimeric histone methyltransferase complex, is essential for NSPC fate determination during postnatal neurogenesis. Deletion of Ash2l in NSPCs impairs their capacity for proliferation and differentiation, leading to simplified dendritic arbors in adult-born hippocampal neurons and deficits in cognitive abilities. RNA sequencing data reveal that Ash2l primarily regulates cell fate specification and neuron commitment. Furthermore, we identified Onecut2, a major downstream target of ASH2L characterized by bivalent histone modifications, and demonstrated that constitutive expression of Onecut2 restores defective proliferation and differentiation of NSPCs in adult Ash2l-deficient mice. Importantly, we identified that Onecut2 modulates TGF-β signaling in NSPCs and that treatment with a TGF-β inhibitor rectifies the phenotype of Ash2l-deficient NSPCs. Collectively, our findings reveal the ASH2L-Onecut2-TGF-β signaling axis that mediates postnatal neurogenesis to maintain proper forebrain function.

References

Yan P, Liu Z, Song M, Wu Z, Xu W, Li K . Genome-wide R-loop Landscapes during Cell Differentiation and Reprogramming. Cell Rep. 2020; 32(1):107870. DOI: 10.1016/j.celrep.2020.107870. View

Urban N, Blomfield I, Guillemot F . Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest. Neuron. 2019; 104(5):834-848. DOI: 10.1016/j.neuron.2019.09.026. View

Stein A, Jones T, Herron T, Patel S, Day S, Noujaim S . Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes. J Clin Invest. 2011; 121(7):2641-50. PMC: 3223825. DOI: 10.1172/JCI44641. View

Xu X, Zheng L, Yuan Q, Zhen G, Crane J, Zhou X . Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res. 2018; 6:2. PMC: 5802812. DOI: 10.1038/s41413-017-0005-4. View

Cho K, Lybrand Z, Ito N, Brulet R, Tafacory F, Zhang L . Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun. 2015; 6:6606. PMC: 4375780. DOI: 10.1038/ncomms7606. View

Lee Y, Ayoub A, Park S, Sha L, Xu J, Mao F . Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin. Nat Commun. 2021; 12(1):2953. PMC: 8134635. DOI: 10.1038/s41467-021-23268-9. View

Perez-Lluch S, Blanco E, Tilgner H, Curado J, Ruiz-Romero M, Corominas M . Absence of canonical marks of active chromatin in developmentally regulated genes. Nat Genet. 2015; 47(10):1158-1167. PMC: 4625605. DOI: 10.1038/ng.3381. View

Wang Y, Guo Y, Tang C, Han X, Xu M, Sun J . Developmental Cytoplasmic-to-Nuclear Translocation of RNA-Binding Protein HuR Is Required for Adult Neurogenesis. Cell Rep. 2019; 29(10):3101-3117.e7. DOI: 10.1016/j.celrep.2019.10.127. View

Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux C, Van Der Smissen P, Dietz H . Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev. 2005; 19(16):1849-54. PMC: 1186184. DOI: 10.1101/gad.340305. View

10.

Karaca E, Harel T, Pehlivan D, Jhangiani S, Gambin T, Akdemir Z . Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015; 88(3):499-513. PMC: 4824012. DOI: 10.1016/j.neuron.2015.09.048. View

11.

Liu C, Gao X, Shi R, Wang Y, He X, Du H . Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice. Cell Prolif. 2023; 56(9):e13439. PMC: 10472527. DOI: 10.1111/cpr.13439. View

12.

Khacho M, Harris R, Slack R . Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci. 2018; 20(1):34-48. DOI: 10.1038/s41583-018-0091-3. View

13.

Li L, Ruan X, Wen C, Chen P, Liu W, Zhu L . The COMPASS Family Protein ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signaling. Cell Rep. 2019; 28(3):698-711.e5. DOI: 10.1016/j.celrep.2019.06.055. View

14.

Bond A, Ming G, Song H . Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later. Cell Stem Cell. 2015; 17(4):385-95. PMC: 4683085. DOI: 10.1016/j.stem.2015.09.003. View

15.

Alam T, Uludag M, Essack M, Salhi A, Ashoor H, Hanks J . FARNA: knowledgebase of inferred functions of non-coding RNA transcripts. Nucleic Acids Res. 2016; 45(5):2838-2848. PMC: 5389649. DOI: 10.1093/nar/gkw973. View

16.

Liu C, Dai S, Shi R, He X, Wang Y, He B . Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration. Glia. 2021; 69(5):1292-1306. DOI: 10.1002/glia.23966. View

17.

Hamilton L, Joppe S, Cochard L, Fernandes K . Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here. Eur J Neurosci. 2013; 37(12):1978-86. DOI: 10.1111/ejn.12207. View

18.

Yu J, Li D, Jiang H . Emerging role of ONECUT2 in tumors. Oncol Lett. 2020; 20(6):328. PMC: 7577075. DOI: 10.3892/ol.2020.12192. View

19.

Hsieh J . Orchestrating transcriptional control of adult neurogenesis. Genes Dev. 2012; 26(10):1010-21. PMC: 3360557. DOI: 10.1101/gad.187336.112. View

20.

Belforte J, Zsiros V, Sklar E, Jiang Z, Yu G, Li Y . Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2009; 13(1):76-83. PMC: 2797836. DOI: 10.1038/nn.2447. View