Genomic map of candidate human imprint control regions: the imprintome

ABSTRACT

Imprinted genes – critical for growth, metabolism, and neuronal function – are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.

KEYWORDS:

• Epigenetics
• genomic imprinting
• foetal origins
• whole genome
• methylation
• imprint control regions

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions:

C.H. and R.L.J. conceived the idea and obtained funding, D.D.J., A.M.R, F.W. and J.H. contributed bioinformatics expertise, D.A.S., A.P., A.L., S.E.C, S.S.P. and M.C. contributed mechanistic expertise to advancing the thesis. All authors contributed to drafting and editing the manuscript.

Data availability

Data will be available from the authors upon request, and at the website https://humanicr.org/.

Ethics statement

These tissues were obtained from the National Institutes of Health funded Laboratory of Human Embryology at the University of Washington, Seattle, WA; they were snap frozen to preserve DNA/RNA integrity (NCSU Institutional Review Board #3565).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2022.2091815

Additional information

Funding

This work was supported in part by National Institutes of Health grants R01HD098857 (D.A.S., C.H., R.L.J.), R01MD011746 (C.H., D.A.S, R.L.J.), R01MD011746-S1 (C.H., D.A.S., R.L.J.), and Office of Extramural Research, National Institutes of Health. R01HD098857, R01MD011746NICHD, NIMHD, NIEHS [R01HD098857, R01MD011746-S1, P30ES025128].