Published February 19, 2021 | Version v1
Journal article Open

hReg-CNCC reconstructs a regulatory network in human cranial neural crest cells and annotates variants in a developmental context

Authors/Creators

  • 1. 1CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of Sciences, Beijing 100190, China 2School of Mathematics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
  • 2. 3Center for Human Genetics, Department of Genetics and Biochemistry, Clemson University, SC 29646, USA; 4Department of Statistics, Department of Biomedical Data Science, Bio-X Program, Stanford University, Stanford, CA 94305, USA;
  • 3. 5Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 6Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 7CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;
  • 4. 8Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; 9Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China;
  • 5. 7CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;10China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China;
  • 6. Department of Statistics, Department of Biomedical Data Science, Bio-X Program, Stanford University, Stanford
  • 7. 1CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of Sciences, Beijing 100190, China; 2School of Mathematics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China;9Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China;11Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 330106, China

Description

Cranial Neural Crest Cells (CNCC) originate at the cephalic region from forebrain, midbrain and hindbrain, migrate into the developing craniofacial region, and subsequently differentiate into multiple cell types. The entire specification, delamination, migration, and differentiation process is highly regulated and abnormalities during this craniofacial development cause birth defects. To better understand the molecular networks underlying CNCC, we integrate paired gene expression & chromatin accessibility data and reconstruct the genome-wide human Regulatory network of Cranial Neural Crest Cells (hReg-CNCC). Consensus optimization predicts high quality regulations and reveals the architecture of upstream, core, and downstream transcription factors that are associated with functions of neural plate border, specification, and migration. hReg-CNCC allows us to annotate genetic variants of human facial GWAS and disease traits with associated cis-regulatory modules, transcription factors, and target genes. For example, we reveal the distal and combinatorial regulation of multiple SNPs to core TF ALX1 and associations to facial distances and disease. In addition, hReg-CNCC connects the DNA sequence differences in evolution, such as ultra-conserved region and human accelerated region, with gene expression and phenotype. hReg-CNCC provides a valuable resource to interpret genetic variant as early as gastrulation during embryonic development.

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