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Review
. 2024 Jun 26;52(3):973-986.
doi: 10.1042/BST20230143.

Differential 3D genome architecture and imprinted gene expression: cause or consequence?

Benoit Moindrot  1 , Yui Imaizumi  2 , Robert Feil  2
Affiliations
Review

Differential 3D genome architecture and imprinted gene expression: cause or consequence?

Benoit Moindrot et al. Biochem Soc Trans. .

Abstract

Imprinted genes provide an attractive paradigm to unravel links between transcription and genome architecture. The parental allele-specific expression of these essential genes - which are clustered in chromosomal domains - is mediated by parental methylation imprints at key regulatory DNA sequences. Recent chromatin conformation capture (3C)-based studies show differential organization of topologically associating domains between the parental chromosomes at imprinted domains, in embryonic stem and differentiated cells. At several imprinted domains, differentially methylated regions show allelic binding of the insulator protein CTCF, and linked focal retention of cohesin, at the non-methylated allele only. This generates differential patterns of chromatin looping between the parental chromosomes, already in the early embryo, and thereby facilitates the allelic gene expression. Recent research evokes also the opposite scenario, in which allelic transcription contributes to the differential genome organization, similarly as reported for imprinted X chromosome inactivation. This may occur through epigenetic effects on CTCF binding, through structural effects of RNA Polymerase II, or through imprinted long non-coding RNAs that have chromatin repressive functions. The emerging picture is that epigenetically-controlled differential genome architecture precedes and facilitates imprinted gene expression during development, and that at some domains, conversely, the mono-allelic gene expression also influences genome architecture.

Keywords: CTCF; chromatin architecture; chromatin loop; genomic imprinting; topologically associating domain.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. CTCF controls allelic sub-TAD organization at several imprinted domains.
(A) The H19-ICR controls imprinting at the Igf2-H19 domain. It comprises four CTCF binding sites — labeled m1-m4 as in [23] — that are methylated on the paternal chromosome, and bound by CTCF on the maternal chromosome. The allele-specific CTCF chromatin immuno-precipitation (ChIP) profiles originate from [33]. Filled lollipops, methylated CpG dinucleotides; open lollipops, unmethylated CpGs. (B) The Igf2-H19 domain comprises the maternally expressed lncRNA gene H19 (imprinted in mesoderm/endoderm), the paternally expressed genes Igf2 (imprinted in mesoderm/endoderm) and Ins2 [imprinted in yolk sac, [109,110]], and the lncRNA gene Nctc1, which shows paternally biaised expression in muscle [92]. Endodermal (EE) and mesodermal enhancers (ME) [green ovals, [92,111]] activate Igf2 on the paternal chromosome through long-distance functional interactions (green arrows). On the maternal chromosome, these interactions are prevented by the CTCF-binding onto the H19-ICR, which acts as a chromatin boundary [23]. On this parental chromosome the enhancers activate H19 (orange arrows). Because of these and other parental-specific chromatin interactions, on the maternal chromosome the domain becomes organized into two sub-TADs (red pyramids), whereas on the paternal chromosome it is within a large overarching TAD (blue pyramid) [2,33]. (C) The Dlk1-Dio3 domain comprises the maternally expressed Meg3, Rian and Mirg non-coding RNAs, the paternally expressed Dlk1 and Rtl1 protein-coding genes, and at its 3′-end, the Dio3 protein-coding gene for which conflicting imprinted statuses have been reported. Maternal CTCF binding occurs at the Meg3-DMR, ∼10 kb downstream the locus’ ICR (IG-DMR). On the maternal allele, CTCF binding at the Meg3-DMR allows for the formation of maternal-specific sub-TAD domains, which are important for the silencing of maternal Dlk1 and Rtl1 allele [33,47]. (D) The Peg13-Kcnk9 domain comprises the Kcnk9 and Trappc9 protein-coding genes, expressed from the maternal allele, and the paternally-expressed Peg13 lncRNA. The locus’ ICR overlaps the Peg13 promoter and is bound by CTCF on the paternal allele. The formation of two sub-TADs on the paternal chromosome prevents functional interaction between enhancers (green) and the Kcnk9 promoter [31]. (E) The Grb10-Ddc domain comprises the maternally expressed Grb10 gene and the paternally expressed Ddc gene, and the biallelically expressed Cobl gene. CTCF binds to the ICR and the CBR2.3 sDMR, on the paternal chromosome exclusively. The formation of two sub-TADs on the paternal chromosome prevents the functional interactions between a putative ME (PME) and the Grb10 promoter, as occurring on the maternal chromosome, while favoring interaction with the paternal Ddc allele [34].
Figure 2.
Figure 2.. Effects of imprinted nuclear lncRNAs on 3D chromatin architecture.
(A) Imprinted lncRNAs can mediate chromatin repression in cis, through the recruitment of chromatin modifiers such as PRC1, PRC2 and G9A (orange ovals) that bring about repressive histone modifications (violet pentagons). This occurs together with the formation of local chromatin 3D architecture (blue parabolas), in a process that may involves liquid-liquid phase separation. The provided example depicts reported in-cis effects in the trophoblast of the lncRNA Kcnq1ot1 (green wave and green shapes) at the Kcnq1 imprinted domain, on the paternal chromosome [73–76,78]. Filled lollipops, methylated CpG dinucleotides; open lollipops, unmethylated CpGs (at the domain's gDMR). (B) The cis-retention of imprinted lncRNAs (green) can affect the degree of compaction on the parental chromosome that is ‘coated’ by the lncRNA (green waves) [71]. This is illustrated for the Igf2r imprinted domain (i.e. the Airn lncRNA), at which long-range contacts are enriched on the paternal chromosome (bottom, in blue) in trophoblast cells, as compared with the maternal chromosome (top, in red), which shows more frequent short-range contacts [88]. These differential contacts contribute to the differential TAD structuration (pyramids) between the parental chromosomes.
Figure 3.
Figure 3.. Models for how allelic transcription and RNA Polymerase II may influence chromatin architecture.
(A) RNA Polymerase II (Pol.II) complexes can influence cohesin-mediated loop extrusion [95,96]. Since many imprinted genes are transcribed strictly from one parental allele only, at imprinted domains this process may confer allele-specific looping events. (B) Transcription factors (green) that associate with DMRs on the unmethylated allele protect against aberrant de novo DNA methylation, thereby maintaining the CTCF binding allelism and allelic 3D-chromatin architecture. This function could be particularly important in early embryonic cells. (C) The elongating form of RNA Polymerase II facilitates H3K36me3 deposition (green pentagones) within the gene body, and, subsequently, the recruitment of the de novo DNA methyltransferases [100,101]. This process might help to maintain methylation at intragenic DMRs, and could thus contributes to the allelic CTCF association at imprinted domains. Filled lollipops, methylated CpG dinucleotides; open lollipops, unmethylated CpGs.
Figure 4.
Figure 4.. Epigenetically-determined somatic maintenance of allele-specific CTCF binding.
The genomic 3D chromatin architecture observed at interphase cells is largely lost at M-phase [104]. In contrast, patterns of DNA methylation persist throughout the cell cycle, including at the DMRs of imprinted domains. The faithful transmission of the allelic DNA methylation at DMRs through M-phase instructs the restauration of the interphase-specific allelic CTCF binding in the daughter cells and its associated (sub-)TAD organization. It provides the epigenetic memory for the developmental maintenance of allelic CTCF binding and its resulting (sub-)TAD organization. Filled lollipops, methylated CpG dinucleotides; open lollipops, unmethylated CpGs.
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