Developmental rewiring of EHMT1 function during human cortical neurogenesis

Abstract

Ubiquitously expressed chromatin regulators orchestrate cell-type-specific gene expression programs, yet how they acquire distinct regulatory functions during development remains fundamentally unresolved. Using temporally controlled protein depletion during human cortical neurogenesis in vitro, we show that the autism-associated histone methyltransferase EHMT1 is developmentally repurposed from epiblast to cortical neurons. Broadly expressed zinc finger proteins recruit EHMT1 to distinct cis-regulatory elements within changing chromatin landscapes associated with lineage-specific transcription factor activity, with extensive remodeling of EHMT1 enhancer occupancy during neural induction dependent on ZNF462. This genomic rewiring is accompanied by a fundamental shift from restraining premature developmental gene expression in pluripotent cells to supporting neuronal programs, with distinct transcriptional consequences of EHMT1 loss across neural progenitors and excitatory and inhibitory neuronal subtypes. Timed depletion and recovery experiments identify the neural progenitor stage as the onset of a developmental period during which EHMT1 is required for faithful neuronal maturation. Remarkably, EHMT1 can re-engage stage-specific targets after prolonged deficiency, allowing extensive transcriptional recovery with only limited molecular scarring. These findings reveal how ubiquitous epigenetic machinery acquires developmental specificity while demonstrating the resilience of developmental gene regulatory programs to prolonged disruption, with implications for neurodevelopmental disorders.

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BibTeX

@misc{kasliwal2026developmental,
  title = {{Developmental rewiring of EHMT1 function during human cortical neurogenesis}},
  author = {K. Kasliwal and K. Chatterjee and V. D. Bocchi and S. R. Mahmood and C. M. Uyehara and W. Marchese and A. Laguillo-Diego and E. Goetzler and G. Theis and A. Minotti and R. M. Walsh and A. Polyzos and E. Apostolou and S. Sidoli and L. Studer and M. Stadtfeld},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.09.757098},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757098v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Developmental rewiring of EHMT1 function during human cortical neurogenesis
AU  - K. Kasliwal
AU  - K. Chatterjee
AU  - V. D. Bocchi
AU  - S. R. Mahmood
AU  - C. M. Uyehara
AU  - W. Marchese
AU  - A. Laguillo-Diego
AU  - E. Goetzler
AU  - G. Theis
AU  - A. Minotti
AU  - R. M. Walsh
AU  - A. Polyzos
AU  - E. Apostolou
AU  - S. Sidoli
AU  - L. Studer
AU  - M. Stadtfeld
PY  - 2026
DA  - 2026/10/09
PB  - bioRxiv
DO  - 10.64898/2026.10.09.757098
UR  - https://www.biorxiv.org/content/10.64898/2026.10.09.757098v1
AB  - Ubiquitously expressed chromatin regulators orchestrate cell-type-specific gene expression programs, yet how they acquire distinct regulatory functions during development remains fundamentally unresolved. Using temporally controlled protein depletion during human cortical neurogenesis in vitro, we show that the autism-associated histone methyltransferase EHMT1 is developmentally repurposed from epiblast to cortical neurons. Broadly expressed zinc finger proteins recruit EHMT1 to distinct cis-regulatory elements within changing chromatin landscapes associated with lineage-specific transcription factor activity, with extensive remodeling of EHMT1 enhancer occupancy during neural induction dependent on ZNF462. This genomic rewiring is accompanied by a fundamental shift from restraining premature developmental gene expression in pluripotent cells to supporting neuronal programs, with distinct transcriptional consequences of EHMT1 loss across neural progenitors and excitatory and inhibitory neuronal subtypes. Timed depletion and recovery experiments identify the neural progenitor stage as the onset of a developmental period during which EHMT1 is required for faithful neuronal maturation. Remarkably, EHMT1 can re-engage stage-specific targets after prolonged deficiency, allowing extensive transcriptional recovery with only limited molecular scarring. These findings reveal how ubiquitous epigenetic machinery acquires developmental specificity while demonstrating the resilience of developmental gene regulatory programs to prolonged disruption, with implications for neurodevelopmental disorders.
ER  -

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