H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1

Abstract

The H19 gene controls the expression of several genes within the Imprinted Gene Network (IGN), involved in growth control of the embryo. However, the underlying mechanisms of this control remain elusive. Here, we identified the methyl-CpG-binding domain protein 1 MBD1 as a physical and functional partner of the H19 long noncoding RNA (lncRNA). The H19 lncRNA-MBD1 complex is required for the control of five genes of the IGN. For three of these genes-Igf2 (insulin-like growth factor 2), Slc38a4 (solute carrier family 38 member 4), and Peg1 (paternally expressed gene 1)-both MBD1 and H3K9me3 binding were detected on their differentially methylated regions. The H19 lncRNA-MBD1 complex, through its interaction with histone lysine methyltransferases, therefore acts by bringing repressive histone marks on the differentially methylated regions of these three direct targets of the H19 gene. Our data suggest that, besides the differential DNA methylation found on the differentially methylated regions of imprinted genes, an additional fine tuning of the expressed allele is achieved by a modulation of the H3K9me3 marks, mediated by the association of the H19 lncRNA with chromatin-modifying complexes, such as MBD1. This results in a precise control of the level of expression of growth factors in the embryo.genomic imprinting | embryonic growth | long noncoding RNA partner | Dlk1 | Cdkn1c

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…According, recent advances sustain an interplay among ICR1 and other iDMRs (our unpublished data) and chromatin interactions between H19 and portions of chromosome 7 [34]. MEST methylation may also be part of an imprinting gene network (IGN), involving the trans -acting functions of H19 lncRNA [35,36]. Further investigations are requested to better elucidate this finding.…”

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 + T-cell immune responses in tuberculosis infection

“…Although heritable changes in gene regulation that occur via modification of the DNA without changes to the DNA sequence are often referred to as epigenetic programming, noncoding RNA (ncRNA)-mediated transcriptional or posttranscriptional regulation is one of the major regulation mechanisms for epigenetic programming (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Recent studies have identified thousands of long ncRNAs (lncRNAs) (17,23) in mammalian genomes that regulate gene expression in a variety of immunological processes (31)(32)(33)(34)(35), such as differentiation of T cells (33,36) and dendritic cells (DCs) (35).…”

Analysis of imprinted messenger RNA expression in deceased transgenic cloned goats

“…H19 is a sensitive imprinted gene, which contains a regulatory domain that is vulnerable to manipulation in vitro (Fauque et al, 2007). Moreover, H19 controls the gene expression of the imprinted gene network by recruiting MBD1, which is involved in individual growth and development (Monnier et al, 2013). The results of previous studies showed that a CpG-island in intron 2 of IGF2R carries a maternal-specific methylation imprint that could act as an imprinting signal to maintain the expression of the maternal allele.…”