Multiomics and deep learning dissect regulatory syntax in human development

Nature · 2026-04-08 · 1 citations

Abstract Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression 1 . Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities 2 . Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis -regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify ‘hard’ syntactic rules requiring precise motif spacing and orientation, ‘soft’ rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis -regulatory logic and interpreting genetic variation during human development.

A Molecular Mechanism for Environmental Context in Protein-Based Epigenetic Memory

SSRN Electronic Journal · 2026-01-01

Genetics and environment distinctively shape the human immune cell epigenome

Nature Genetics · 2026-01-27 · 3 citations

The epigenome of human immune cells is shaped by both genetics and environmental factors, yet the relative contributions of these influences remain incompletely characterized. Here we use single-nucleus methylation sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to systematically explore how pathogen and chemical exposures, along with genetic variation, are associated with changes in the immune cell epigenome. Distinct exposure-associated differentially methylated regions (eDMRs) and differentially accessible regions were identified, and a significant correlation between these two modalities was observed. Additionally, genotype-associated DMRs (gDMRs) were detected, indicating that eDMRs are enriched in regulatory regions, whereas gDMRs are preferentially located within gene body marks. Disease-associated single-nucleotide polymorphisms were frequently colocalized with methylation quantitative trait loci, providing cell-type-specific insights into the genetic basis of diseases. These findings highlight the complex interplay between genetic and environmental factors in shaping the immune cell epigenome and advance understanding of immune cell regulation in health and disease.

Table S17 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>Differential chromatin accessibility in sgKat7 relative to sgSafe-transduced neoplastic cells using consensus regions</p>

Table S16 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>Differential chromatin accessibility regions of sgPsip1 relative to sgSafe cells</p>

Table S19 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>Motif analysis of overlapping regions with increased chromatin accessibility</p>

Table S11 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>Sample information for bulk ATAC-seq</p>

Table S28 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>Tumor metrics of the Lenti-U6BCsgRNAEpistasis/Cre vectors</p>

Table S20 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>DGE of KP787 cell line treated with WM3835 relative to DMSO</p>

Table S22 from Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes

2025-12-02

<p>scRNA-seq DGE analysis</p>