A single epigenetic repressor controls opposing developmental tempos in human neural and cranial neural crest lineages
- 1Department of Cancer Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
Abstract
The precise timing of lineage specification is essential for embryonic development, yet the epigenetic mechanisms enforcing human developmental tempo remain poorly understood. Heterozygous loss-of-function variants in ZNF462 cause Weiss-Kruszka syndrome (WKS), a pleiotropic disorder characterized by neurodevelopmental delays and craniofacial dysmorphisms. Here, we show that ZNF462 acts as an epigenetic gatekeeper that coordinates human developmental tempo across divergent lineages by repressing cell lineage-specific gene enhancers. In human embryonic stem cells (hESCs), ZNF462 maintains self-renewal by recruiting the G9A/GLP histone methyltransferase complex to silence primate-specific retrotransposon-derived enhancers. Upon neural lineage commitment, ZNF462 redirects to hominoid-specific LTR5_Hs elements and divergent lineage-specific enhancer programs, where its loss produces opposing kinetics. In neural progenitor cells (NPCs), ZNF462 enforces G9A/GLP-dependent repression of ZIC-driven neural enhancers, and loss of this repression traps NPCs in a progenitor state, slowing cortical neurogenesis without impairing terminal neurogenic capacity. In neural crest cells (NCCs), ZNF462 targets repressive chromatin to silence SOX9 family-driven enhancers. Here, ZNF462 haploinsufficiency triggers premature activation of definitive NCC specifiers, accelerating differentiation. These findings establish that a single repressor can simultaneously decelerate and accelerate developmental tempo by gating lineage-specific enhancers, placing Weiss-Kruszka syndrome into the emerging class of human developmental timing disorders.
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BibTeX
@misc{bell2026single,
title = {{A single epigenetic repressor controls opposing developmental tempos in human neural and cranial neural crest lineages}},
author = {O. Bell and Z. E. Atmaca Duran and M. Birtele and G. Quadrato and S. Mendiratta and R. Yelagandula and C. Stevens and S. Rhie},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.758088},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.758088v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A single epigenetic repressor controls opposing developmental tempos in human neural and cranial neural crest lineages
AU - O. Bell
AU - Z. E. Atmaca Duran
AU - M. Birtele
AU - G. Quadrato
AU - S. Mendiratta
AU - R. Yelagandula
AU - C. Stevens
AU - S. Rhie
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.758088
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.758088v1
AB - The precise timing of lineage specification is essential for embryonic development, yet the epigenetic mechanisms enforcing human developmental tempo remain poorly understood. Heterozygous loss-of-function variants in ZNF462 cause Weiss-Kruszka syndrome (WKS), a pleiotropic disorder characterized by neurodevelopmental delays and craniofacial dysmorphisms. Here, we show that ZNF462 acts as an epigenetic gatekeeper that coordinates human developmental tempo across divergent lineages by repressing cell lineage-specific gene enhancers. In human embryonic stem cells (hESCs), ZNF462 maintains self-renewal by recruiting the G9A/GLP histone methyltransferase complex to silence primate-specific retrotransposon-derived enhancers. Upon neural lineage commitment, ZNF462 redirects to hominoid-specific LTR5_Hs elements and divergent lineage-specific enhancer programs, where its loss produces opposing kinetics. In neural progenitor cells (NPCs), ZNF462 enforces G9A/GLP-dependent repression of ZIC-driven neural enhancers, and loss of this repression traps NPCs in a progenitor state, slowing cortical neurogenesis without impairing terminal neurogenic capacity. In neural crest cells (NCCs), ZNF462 targets repressive chromatin to silence SOX9 family-driven enhancers. Here, ZNF462 haploinsufficiency triggers premature activation of definitive NCC specifiers, accelerating differentiation. These findings establish that a single repressor can simultaneously decelerate and accelerate developmental tempo by gating lineage-specific enhancers, placing Weiss-Kruszka syndrome into the emerging class of human developmental timing disorders.
ER -