The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta

TLDR

Imprinted genes are essential for mammalian development, yet the precise number of imprinted genes in the human genome remains uncertain. We discovered that the chromosome 19 microRNA cluster (C19MC) is imprinted in the placenta, with only the paternal allele expressed; a maternally methylated DMR upstream of the cluster generates diverse non‑coding RNAs and positions C19MC adjacent to the imprinted ZNF331 gene, adding a novel primate‑specific imprinted domain to the repertoire of small ncRNA clusters.

Abstract

Imprinted genes play crucial roles in mammalian development and disruption of their expression is associated with many human disorders including tumourigenesis; yet, the actual number of imprinted genes in the human genome remains a matter of debate. Here, we report on the unexpected finding that the chromosome 19 microRNA cluster (C19MC), the largest human microRNA gene cluster discovered so far, is regulated by genomic imprinting with only the paternally inherited allele being expressed in the placenta. DNA methylation profiling identified a differentially methylated region (C19MC-DMR1) that overlaps an upstream CpG-rich promoter region associated with short tandem repeats. It displays a maternal-specific methylation imprint acquired in oocytes and generates a complex population of large, compartimentalized non-coding RNA (ncRNA) species retained in close proximity to the C19MC transcription site. This occurs adjacent to, but not within, a poorly characterized nuclear Alu-rich domain. Interestingly, C19MC maps near another imprinted gene, the maternally expressed ZNF331 gene, and therefore may define a novel, previously unrecognized large imprinted primate-specific chromosomal domain. Altogether, our study adds C19MC to the growing list of imprinted repeated small RNA gene clusters and further strengthens the potential involvement of small ncRNAs in the function and/or the evolution of imprinted gene networks.