Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway

Cell Death & Differentiation volume 30, pages 1943–1956 (2023)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Ash2l is essential for the maintenance of proliferation and differentiation of NSPCs.
Fig. 2: Ablation of Ash2l in NSPCs impairs adult neurogenesis.
Fig. 3: Ash2l depletion impairs hippocampus-associated behaviors of adult mice.
Fig. 4: Global changes in gene expression and histone marks upon Ash2l deletion.
Fig. 5: Overexpression of OC2 promotes NSPCs proliferation and differentiation.
Fig. 6: OC2 is a main downstream effector of Ash2l and maintains NSPC fate determination.
Fig. 7: Inhibition of TGF-β signaling restores defective adult neurogenesis in Ash2l-deficient mice.

Similar content being viewed by others

Data availability

The RNA‑sequencing data have been deposited in the NCBI GEO database and are available under the accession number GSE234685. The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Lui JH, Hansen DV, Kriegstein AR. Development and evolution of the human neocortex. Cell. 2011;146:18–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu PP, Tang GB, Xu YJ, Zeng YQ, Zhang SF, Du HZ, et al. MiR-203 interplays with polycomb repressive complexes to regulate the proliferation of neural stem/progenitor cells. Stem Cell Rep. 2017;9:190–202.

    Article  CAS  Google Scholar 

  3. Wang Y, Guo Y, Tang C, Han X, Xu M, Sun J, et al. Developmental cytoplasmic-to-nuclear translocation of RNA-binding protein HuR is required for adult neurogenesis. Cell Rep. 2019;29:3101–17.e3107.

    Article  CAS  PubMed  Google Scholar 

  4. Montalban-Loro R, Lassi G, Lozano-Urena A, Perez-Villalba A, Jimenez-Villalba E, Charalambous M, et al. Dlk1 dosage regulates hippocampal neurogenesis and cognition. Proc Natl Acad Sci USA. 2021;118:e2015505118.

  5. Khacho M, Harris R, Slack RS. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci. 2019;20:34–48.

    Article  CAS  PubMed  Google Scholar 

  6. Liu PP, Xu YJ, Teng ZQ, Liu CM. Polycomb repressive complex 2: emerging roles in the central nervous system. Neuroscientist. 2018;24:208–20.

    Article  PubMed  Google Scholar 

  7. Roidl D, Hacker C. Histone methylation during neural development. Cell Tissue Res. 2014;356:539–52.

    Article  CAS  PubMed  Google Scholar 

  8. Kuroda MI, Kang H, De S, Kassis JA. Dynamic competition of polycomb and trithorax in transcriptional programming. Annu Rev Biochem. 2020;89:235–53.

  9. Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171:34–57.

    Article  CAS  PubMed  Google Scholar 

  10. Liu PP, Xu YJ, Dai SK, Du HZ, Wang YY, Li XG, et al. Polycomb protein EED regulates neuronal differentiation through targeting SOX11 in hippocampal dentate gyrus. Stem Cell Rep. 2019;13:115–31.

    Article  CAS  Google Scholar 

  11. Jiang H. The complex activities of the SET1/MLL complex core subunits in development and disease. Biochim Biophys Acta Gene Regul Mech. 2020;1863:194560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee YT, Ayoub A, Park SH, Sha L, Xu J, Mao F, et al. Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin. Nat Commun. 2021;12:2953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fossati A, Dolfini D, Donati G, Mantovani R. NF-Y recruits Ash2L to impart H3K4 trimethylation on CCAAT promoters. PLoS ONE. 2011;6:e17220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harikumar A, Meshorer E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 2015;16:1609–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu J, Wu X, Zhang H, Pfeifer GP, Lu Q. Dynamics of RNA polymerase II pausing and bivalent histone H3 methylation during neuronal differentiation in brain development. Cell Rep. 2017;20:1307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bochynska A, Luscher-Firzlaff J, Luscher B. Modes of interaction of KMT2 histone H3 lysine 4 methyltransferase/COMPASS complexes with chromatin. Cells. 2018;7:17.

  17. Stein AB, Jones TA, Herron TJ, Patel SR, Day SM, Noujaim SF, et al. Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes. J Clin Invest. 2011;121:2641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bertero A, Madrigal P, Galli A, Hubner NC, Moreno I, Burks D, et al. Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev. 2015;29:702–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen K, Chen Z, Wu D, Zhang L, Lin X, Su J, et al. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat Genet. 2015;47:1149–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Campbell SA, McDonald CL, Krentz NAJ, Lynn FC, Hoffman BG. TrxG complex catalytic and non-catalytic activity play distinct roles in pancreas progenitor specification and differentiation. Cell Rep. 2019;28:1830–44.e1836.

    Article  CAS  PubMed  Google Scholar 

  21. Pérez-Lluch S, Blanco E, Tilgner H, Curado J, Ruiz-Romero M, Corominas M, et al. Absence of canonical marks of active chromatin in developmentally regulated genes. Nat Genet. 2015;47:1158–67.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wan M, Liang J, Xiong Y, Shi F, Zhang Y, Lu W, et al. The trithorax group protein Ash2l is essential for pluripotency and maintaining open chromatin in embryonic stem cells. J Biol Chem. 2013;288:5039–48.

    Article  CAS  PubMed  Google Scholar 

  23. Tsai PH, Chien Y, Wang ML, Hsu CH, Laurent B, Chou SJ, et al. Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network. Nucleic Acids Res. 2019;47:10115–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luscher-Firzlaff J, Chatain N, Kuo CC, Braunschweig T, Bochynska A, Ullius A, et al. Hematopoietic stem and progenitor cell proliferation and differentiation requires the trithorax protein Ash2l. Sci Rep. 2019;9:8262.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li L, Ruan X, Wen C, Chen P, Liu W, Zhu L, et al. The COMPASS family protein ASH2L mediates corticogenesis via transcriptional regulation of Wnt signaling. Cell Rep. 2019;28:698–711 e695.

    Article  CAS  PubMed  Google Scholar 

  26. Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z, et al. Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron. 2015;88:499–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao C, Teng EM, Summers RG Jr., Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol. 2015;7:a018812.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bond AM, Ming GL, Song H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell. 2015;17:385–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hsieh J. Orchestrating transcriptional control of adult neurogenesis. Genes Dev. 2012;26:1010–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Alam T, Uludag M, Essack M, Salhi A, Ashoor H, Hanks JB, et al. FARNA: knowledgebase of inferred functions of non-coding RNA transcripts. Nucleic Acids Res. 2017;45:2838–48.

    CAS  PubMed  Google Scholar 

  32. Yu J, Li D, Jiang H. Emerging role of ONECUT2 in tumors. Oncol Lett. 2020;20:328.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dai SK, Liu PP, Du HZ, Liu X, Xu YJ, Liu C, et al. Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters. EMBO Rep. 2021;22:e52023.

  34. Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux CE, Van der Smissen P, Dietz HC, et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev. 2005;19:1849–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vander Ark A, Cao J, Li X. TGF-beta receptors: In and beyond TGF-beta signaling. Cell Signal. 2018;52:112–20.

    Article  Google Scholar 

  36. Vogel T, Ahrens S, Buttner N, Krieglstein K. Transforming growth factor beta promotes neuronal cell fate of mouse cortical and hippocampal progenitors in vitro and in vivo: identification of Nedd9 as an essential signaling component. Cereb Cortex. 2010;20:661–71.

    Article  PubMed  Google Scholar 

  37. Hamaguchi M, Muramatsu R, Fujimura H, Mochizuki H, Kataoka H, Yamashita T. Circulating transforming growth factor-beta1 facilitates remyelination in the adult central nervous system. Elife. 2019;8:e41869.

  38. Mirzamohammadi F, Papaioannou G, Inloes JB, Rankin EB, Xie H, Schipani E, et al. Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-beta signalling. Nat Commun. 2016;7:12047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Urban N, Blomfield IM, Guillemot F. Quiescence of adult mammalian neural stem cells: a highly regulated rest. Neuron. 2019;104:834–48.

    Article  CAS  PubMed  Google Scholar 

  40. Yang QQ, Zhai YQ, Wang HF, Cai YC, Ma XY, Yin YQ, et al. Nuclear isoform of FGF13 regulates post-natal neurogenesis in the hippocampus through an epigenomic mechanism. Cell Rep. 2021;35:109127.

    Article  CAS  PubMed  Google Scholar 

  41. Hamilton LK, Joppe SE, L MC, Fernandes KJ. Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here. Eur J Neurosci. 2013;37:1978–86.

    Article  PubMed  Google Scholar 

  42. Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun. 2015;6:6606.

    Article  CAS  PubMed  Google Scholar 

  43. Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci. 2017;18:335–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Luna VM, Anacker C, Burghardt NS, Khandaker H, Andreu V, Millette A, et al. Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus. Science. 2019;364:578–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ma H, Su L, Xia W, Wang W, Tan G, Jiao J. MacroH2A1.2 deficiency leads to neural stem cell differentiation defects and autism-like behaviors. EMBO Rep. 2021;22:e52150.

  46. Sapkota D, Chintala H, Wu F, Fliesler SJ, Hu Z, Mu X. Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development. Proc Natl Acad Sci USA. 2014;111:E4086–4095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. van der Raadt J, van Gestel SHC, Nadif Kasri N, Albers CA. ONECUT transcription factors induce neuronal characteristics and remodel chromatin accessibility. Nucleic Acids Res. 2019;47:5587–602.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mullen AC, Wrana JL. TGF-beta family signaling in embryonic and somatic stem-cell renewal and differentiation. Cold Spring Harb Perspect Biol. 2017;9:a022186.

  49. Kalkman HO. Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia. Pharmacol Ther. 2009;121:115–22.

    Article  CAS  PubMed  Google Scholar 

  50. Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, et al. Transforming growth factor-beta in stem cells and tissue homeostasis. Bone Res. 2018;6:2.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Yan P, Liu Z, Song M, Wu Z, Xu W, Li K, et al. Genome-wide R-loop landscapes during cell differentiation and reprogramming. Cell Rep. 2020;32:107870.

    Article  CAS  PubMed  Google Scholar 

  52. Fu S, Wang Q, Moore JE, Purcaro MJ, Pratt HE, Fan K, et al. Differential analysis of chromatin accessibility and histone modifications for predicting mouse developmental enhancers. Nucleic Acids Res. 2018;46:11184–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu C, Dai SK, Shi RX, He XC, Wang YY, He BD, et al. Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration. Glia. 2021;69:1292–306.

    Article  PubMed  Google Scholar 

  54. Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 2010;6:433–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2010;13:76–83.

    Article  CAS  PubMed  Google Scholar 

  56. Liu C, Gao X, Shi RX, Wang YY, He XC, Du HZ, et al. Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice. Cell Prolif. 2023: e13439. https://doi.org/10.1111/cpr.13439.

Download references

Funding

This work was supported by grants from the National Key Research and Development Program of China Project (2021YFA1101400), the Informatization Plan of Chinese Academy of Sciences (CAS-WX2021SF-0301), the National Science Foundation of China (82271428), and the Open Project Program of State Key Laboratory of Stem Cell and Reproductive Biology.

Author information

Authors and Affiliations

  1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China

    Ya-Jie Xu, Shang-Kun Dai, Chun-Hui Duan, Zi-Han Zhang, Pei-Pei Liu, Cong Liu, Hong-Zhen Du, Xu-Kun Lu, Lei Li, Zhao-Qian Teng & Chang-Mei Liu

  2. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China

    Ya-Jie Xu, Shang-Kun Dai, Chun-Hui Duan, Zi-Han Zhang, Pei-Pei Liu, Cong Liu, Hong-Zhen Du, Xu-Kun Lu, Lei Li, Zhao-Qian Teng & Chang-Mei Liu

  3. Beijing Institute for Stem Cell and Regenerative Medicine, 100101, Beijing, China

    Ya-Jie Xu, Shang-Kun Dai, Chun-Hui Duan, Zi-Han Zhang, Pei-Pei Liu, Cong Liu, Hong-Zhen Du, Xu-Kun Lu, Lei Li, Zhao-Qian Teng & Chang-Mei Liu

  4. Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, 215000, Suzhou, China

    Shijun Hu

  5. Savaid Medical School, University of Chinese Academy of Sciences, 100049, Beijing, China

    Lei Li, Zhao-Qian Teng & Chang-Mei Liu

Authors
  1. Ya-Jie Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shang-Kun Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chun-Hui Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zi-Han Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pei-Pei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong-Zhen Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xu-Kun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shijun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhao-Qian Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chang-Mei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YJX and CML, conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; SKD, CHD, ZHZ, PPL, CL, HZD., and ZQT collection and assembly of data. XKL, SJH, and LL, generation of Ash2l conditional knockout mice.

Corresponding authors

Correspondence to Zhao-Qian Teng or Chang-Mei Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

Our studies did not include human participants, human data, or human tissue.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, YJ., Dai, SK., Duan, CH. et al. ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway. Cell Death Differ 30, 1943–1956 (2023). https://doi.org/10.1038/s41418-023-01189-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41418-023-01189-y

Search

Advanced search

Quick links