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<p>The cerebellar rhombic lip (RL) of the prenatal hindbrain is a progenitor niche essential for cerebellar glutamatergic neurogenesis. Humans demonstrate a structural elaboration of this niche with a rhombic lip subventricular zone (RL-SVZ). Disruption of this zone causes cerebellar malformations and tumors, yet its gene regulatory networks are poorly understood. We present a predicted gene regulatory network for the human RL inferred from epigenomic maps of the developing human cerebellum. We generated DNA methylomes from microdissected mid-gestation human RL ventricular zone (RL-VZ) and RL-SVZ (<i>N</i> = 9; 15–16 post-conception weeks) using low-input Enzymatic MethylSeq, and profiled histone marks of active promoters and enhancers in whole fetal cerebellum (<i>N</i> = 6; 14 and 18 weeks). Transition from RL-VZ to RL-SVZ is accompanied by widespread hypomethylation, including 9,855 differentially methylated regions (DMRs) enriched for binding sites of ATOH1, NEUROD1/2, and HMGA1. Of these, 88.9% are hypomethylated in RL-SVZ, enriched in active enhancers and human accelerated regions, and depleted at promoters. By integrating DMRs with bulk tissue histone maps as well as single-cell chromatin accessibility and transcriptomic maps of the mid-gestation cerebellum, we inferred over 100,000 transcription factor–enhancer–gene links. Twenty-five DMRs overlap human accelerated regions near genes implicated in intellectual disability, autism spectrum disorder, and neurological deficits. DMRs are also enriched in copy-number aberrations in medulloblastoma, with ~ 25% overlapping known aberrant regions, nominating disrupted promoters and enhancers. These data provide a framework for interpreting non-coding variation in human cerebellar development and disease.</p>

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Differentially Methylated Regions in Human Rhombic Lip Compartments Are Enriched in Putative Active Enhancers, Human Accelerated Regions, and Medulloblastoma Copy Number Aberrations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Xinghan Sun,
  • Soumya Menon,
  • Paul Wambo,
  • Ilinca Lungu,
  • Kimberly A. Aldinger,
  • Shraddha Pai

摘要

The cerebellar rhombic lip (RL) of the prenatal hindbrain is a progenitor niche essential for cerebellar glutamatergic neurogenesis. Humans demonstrate a structural elaboration of this niche with a rhombic lip subventricular zone (RL-SVZ). Disruption of this zone causes cerebellar malformations and tumors, yet its gene regulatory networks are poorly understood. We present a predicted gene regulatory network for the human RL inferred from epigenomic maps of the developing human cerebellum. We generated DNA methylomes from microdissected mid-gestation human RL ventricular zone (RL-VZ) and RL-SVZ (N = 9; 15–16 post-conception weeks) using low-input Enzymatic MethylSeq, and profiled histone marks of active promoters and enhancers in whole fetal cerebellum (N = 6; 14 and 18 weeks). Transition from RL-VZ to RL-SVZ is accompanied by widespread hypomethylation, including 9,855 differentially methylated regions (DMRs) enriched for binding sites of ATOH1, NEUROD1/2, and HMGA1. Of these, 88.9% are hypomethylated in RL-SVZ, enriched in active enhancers and human accelerated regions, and depleted at promoters. By integrating DMRs with bulk tissue histone maps as well as single-cell chromatin accessibility and transcriptomic maps of the mid-gestation cerebellum, we inferred over 100,000 transcription factor–enhancer–gene links. Twenty-five DMRs overlap human accelerated regions near genes implicated in intellectual disability, autism spectrum disorder, and neurological deficits. DMRs are also enriched in copy-number aberrations in medulloblastoma, with ~ 25% overlapping known aberrant regions, nominating disrupted promoters and enhancers. These data provide a framework for interpreting non-coding variation in human cerebellar development and disease.