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Michael J. O'Neill, The influence of non-coding RNAs on allele-specific gene expression in mammals, Human Molecular Genetics, Volume 14, Issue suppl_1, 15 April 2005, Pages R113–R120, https://doi.org/10.1093/hmg/ddi108
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Abstract
Current research has revealed that the influence of RNA molecules on gene expression reaches beyond the realm of protein synthesis back into the nucleus, where it not only dictates the transcriptional activity of genes, but also shapes the chromatin architecture of extensive regions of DNA. Non-coding RNA, in the context of this review, refers to transcripts expressed and processed in the nucleus much like any protein coding gene, but lacking an open reading frame and often transcribed antisense to bona fide protein coding genes. In mammals, these types of transcripts are highly coincident with allele-specific silencing of imprinted genes and have a proven role in dosage compensation via X-inactivation. The biochemistry of how non-coding RNAs regulate transcription is the subject of intense research in both prokaryotic and eukaryotic models. Mechanisms such as RNA interference may have deep phylogenetic roots, but their relevance to imprinting and X-inactivation in mammals has not been proven. The remarkable diversity of non-coding transcription associated with parent-of-origin directed gene silencing hints at an equally diverse assortment of mechanisms.
INTRODUCTION
Despite pronouncements to the contrary, consensus is currently an elusive concept. The difficulty emanates from differences that are likely born of a conflict at the core of our identity. The divisions run deep and wide, from discord between neighbors so near they overlap to antagonism between participants so remote they would seem insignificant to one another. In addition, we ponder the influence of what once were thought merely to be passive purveyors of information. We, of course, are not speaking of our identity in regards to party affiliation, but rather phylogenetic affiliation of our identity as mammals. The conflict is not a political one, but an intragenomic one; the antagonism is not ideological but epigenetic and the influential purveyors not media conglomerates but non-coding RNAs. And to put the metaphor to rest, the lack of consensus stems not from a profusion of irreconcilable cultural mores, but from our inability to arrive at a mechanistic consensus about the role, in mammals, of non-coding RNAs in the regulation of gene expression. This review attempts to gather much of the current knowledge about non-coding RNAs involved in parent-of-origin specific expression at eight heavily studied loci in mammals (Table 1). Each of these loci are subject to genomic imprinting: the epigenetic marking of alleles through differential cytosine methylation or chromatin modifications, which result in allele-specific transcriptional silencing during embryonic development. The limitations of space in the face of the extraordinarily complex nature of transcriptional regulation at these loci, involving far more than the production of non-coding RNAs, insure that this review will unfortunately give short shrift to the brilliant work of many. With apologies to those left out, it is hoped that this review may at least serve as a sort of crib sheet for students in the field. For more thorough reviews about the individual topics, readers are referred to work of Verona et al. (1) and Peters and Beechey (2) for genomic imprinting; Plath et al. (3) and Meard (4) for X-inactivation and Lippman and Martienssen (5) and Lavorgna et al. (6) for non-coding RNA.
IGF2/H19 LOCUS
This cluster (human 11p15.5 and mouse distal 7) was not only the first imprinted locus to be identified (7), but also provided the first example of a spliced, poly-adenylated non-coding RNA ever identified, H19 (8). This locus features reciprocal imprinted expression of H19 (maternally active) (9) and IGF2 (paternally active) (Fig. 1A). Mutations disrupting imprinted expression of IGF2 underlie a substantial proportion of cases of the congenital growth disorder, Beckwith–Wiedemann syndrome (BWS) in humans (see KCNQ1 locus subsequently) (10,11). A great deal of work over the past 15 years involving genetic manipulation of this locus in mice indicates that the H19 transcript itself has no apparent role in the imprinted expression of its neighboring genes. Most compelling of these experiments was a ‘clean’ knockout of H19 in mice, leaving the promoter and surrounding transcription unit intact but removing the entirety of the RNA coding sequence (12). The clean knockout had no discernable phenotype and no effect on the imprinted expression of Igf2. Several studies (13–15) show that the key imprinting control element for this locus is a differentially methylated domain (DMD) 2–4 kb upstream of the H19 transcription start, the H19-DMD. Four repeat units within the DMD contain closely apposed but separable DNA elements, which attract CpG methylation or bind the chromatin insulator nucleating factor, CTCF (16,17). The presence of methylated CpGs in the DMD on the paternal chromosome prevents the assembly of the insulator and allows enhancers downstream of H19 to interact with the promoter of Igf2, driving its expression in a tissue-specific manner (18). The dispensability of the H19 transcript to the imprinted expression of Igf2 and to the normal mouse development suggests that the RNA may be non-functional. The relatively high sequence conservation of H19 among mammals (77% identity between human and mouse) (8), however, indicates that the gene is subject to purifying selection, a hallmark of functional sequences. In addition to H19, other non-coding RNAs emanating from transcription units in the Igf2/H19 region have been identified (19,20). Some of these are expressed in an imprinted fashion, whereas others are expressed bi-allelically, but their role in the transcriptional activity of this locus is currently unknown.
IGF2R/M6PR LOCUS
A key element of the growth regulatory axis of IGF2 is the IGF2 receptor (IGF2R/M6PR), an antagonist of IGF2 mitogenic activity (21). This is the gene, which acquired the ability to bind IGF2 at some point in the early history of mammals, perhaps coincident with the adaptation to gestational maternal provisioning and also with the evolution of genomic imprinting (22). Igf2r, located on proximal chromosome 17 in mice, is transcribed only from the maternal chromosome in embryos (23) (Fig. 1B). IGF2R, mapping to 6q25.3, carries a parent-specific methylation mark, but has been shown to be expressed bi-allelically in primates (24). Like most imprinted genes, Igf2r exists in a cluster of other imprinted genes. A differentially methylated region (DMR) within the second intron of Igf2r constitutes a critical, bi-directional element controlling paternal allele silencing of three protein coding imprinted genes at this locus, Igf2r, Slc22a2 and Slc22a3 (25). The DMR resides in a promoter that drives transcription from the paternal chromosome of a non-coding, spliced, antisense transcript, Air, which partially overlaps Igf2r. Barlow and coworkers (26) have shown by strategic gene knockouts and exogenous promoter insertions that Air is essential to the silencing not only of Igf2r but also of Slc22a2 and Slc22a3. What has become clear from these experiments is that the silencing of Igf2r is affected not merely by the activity of the Air promoter, i.e. by promoter competition or occlusion, but that the silencing of Igf2r and the downstream Slc22a2 and Slc22a3 require the production of the Air transcript (27). Deletion of the majority of the Air sequence in mice, while leaving its promoter intact, abolishes paternal silencing of Igf2r, Slc22a2 and Slc22a3. Replacement of the Igf2r promoter with an exogenous promoter, or deleting it outright, has no effect on the ability of Air transcription to effect silencing of Slc22a2 and Slc22a3. At present, the mechanism by which Air silences its neighbors in cis is not known. It has been suggested that the Air transcript acts in a similar way to Xist, the non-coding RNA mediator of X-chromosome inactivation (discussed subsequently). Perhaps, future experiments will determine whether, like Xist, Air RNA acts in cis by coating adjacent sequences and recruiting heterochromatinizing factors.
KCNQ1 LOCUS
As with the closely linked IGF2/H19 cluster, genetic and epigenetic mutations in this cluster of imprinted genes at human 11p15.5, and distal mouse chromosome 7, are implicated in BWS (28). KCNQ1 is centrally located among eight maternally expressed imprinted genes in a region spanning ∼1 Mb (29) (Fig. 1C). Paternal chromosome silencing of these genes, as in the Igf2r locus, relies on a DMR (KvDMR1 or IC2) with bi-directional regulatory influence (30). This DMR lies within intron 10 of KCNQ1 and resides in the promoter for a non-coding, spliced, antisense transcript, KCNQ1ot1, spanning ∼60 kb in human (∼54 kb in mouse) within the KCNQ1 gene. In mice, deletion of this DMR results in the loss of expression of the antisense transcript and activation of the normally paternally silent genes, when the deletion is paternally transmitted (31). Similarly, loss of allele-specific methylation of the DMR on the paternal chromosome in human patients with BWS leads to activation of these genes (32).
Recently, Reik and coworkers (33) showed that a few genes lying at a distance both telomeric and centromeric to Kcnq1 retain paternal-specific repression in placenta of mice lacking genome-wide CpG methylation (Dnmt1−/− mice). Intriguingly, these genes (Ascl2, Tssc4, Cd81 and Osbpl5), which retain paternal silencing in the absence of methylation, are all subject to paternal activation in the absence of the KvDMR. Obviously, a component critical to the silencing of these genes remains in the absence of methylation. As with Air, the Kcnq1 antisense transcript has been proposed to be an active player in the paternal silencing of this locus, but unlike the former, mouse mutants uncoupling the activity of the DMR from the production of the antisense transcript have not yet been reported. Kanduri and coworkers (34) have shown, however, that the Kcnq1ot1 transcript is required for bi-directional silencing of both overlapping and non-overlapping reporter genes in an episome-based system.
DLK1-GTL2 LOCUS
This locus, located on human 14q32/mouse distal 12, and also spanning nearly 1 Mb, represents a point of departure from imprinted clusters exhibiting a single, however, critical, non-coding transcript (Fig. 1D). Allele-specific transcription in this region consists of two paternally active protein coding genes (DLK1 and DIO3), a paternally active retroposon-like gene (RTL1), a maternally active antisense transcript complementary to RTL1 (antiRTL1), a maternally active cluster of small nucleolar RNAs (C/D box snoRNAs), several maternally active microRNA encoding genes and a maternal transcription of a spliced, antisense transcript complementary to DIO3 (35–41) (Fig. 1D). Imprinted expression in this region hinges upon a bi-directionally active DMR located between DLK1 and GTL2, which influences transcriptional activity throughout the cluster. Deletion of this DMR in mice, termed IG-DMR (for intergenic, germline DMR), represses all of the maternal-specific transcripts and activates Dlk1 (42). The IG-DMR deletion is perinatally lethal when transmitted maternally, yet has no effect when paternally transmitted. This is unusual in that the DMR is normally unmethylated on the maternal chromosome and methylated on the paternal chromosome. Some intrinsic properties of the DMR sequence, masked by methylation, are crucial to maternal-specific transcription. Perhaps, like the H19-DMD, the IG-DMR acts as a chromatin insulator.
A compelling mystery is the role of the imprinted micro-RNAs in this region. The strongest hint of their importance to regulation of expression at this locus comes from studies of the etiology of the callipyge (CLPG) mutation in sheep. CLPG is a polar overdominant mutation, characterized by postnatal hypertrophy of skeletal muscle in heterozygotes, only when CLPG is inherited paternally (43). Maternal heterozygotes and homozygotes are phenotypically normal. The genetic lesion in CLPG is an A/G transition in a highly conserved dodecamer motif lying in close proximity to the IG-DMR (44). The muscle hypertrophy evidently results from expression of DLK1 in skeletal muscle owing to a long range controlling element (LRCE) (45). LRCE apparently becomes activated ectopically in muscle by virtue of the A/G transition mutation. When transmitted maternally, the LRCE influence is directed centromerically activating the micro-RNA clusters. Why, then, are homozygotes, which would be expressing both DLK1 paternally and the micro-RNAs maternally, be phenotypically normal? The implication is that the micro-RNAs act post-trancriptionally and in trans, to effect the degradation of the ectopic DLK1 transcripts. Thus far, this is the strongest evidence of the involvement of RNA interference (RNAi) (discussed subsequently) in the regulation of imprinted genes.
PWS/AS LOCUS
Prader–Willi (PWS) and Angelman (AS) syndromes are the result of disrupted expression of imprinted genes covering >4 Mb at human 15q11–13 (mouse proximal 7) (46–50). PWS is characterized in newborns by hypotonia, hypogonadism, variable mental retardardation and feeding difficulties followed later in childhood by hyperphagia (51). PWS is a continuous gene disorder manifested by loss of expression of a group of paternally transcribed protein-coding genes including SNURF/SNRPN, NECDIN, MKRN3, MAGEL2 and ZNF127 (Fig. 1E). AS is characterized by ataxic gate, jerky arm movements, inappropriate laughter and severe mental retardation (52). Loss-of-function mutations in a maternally transcribed gene at this locus, UBE3A, can cause AS (53,54), but the more frequent cause is maternal transmission of large deletions in this region. A second maternal specific transcript from this region, ATP10C, has also been implicated in the AS phenotype (55). Maternal silencing of the PWS genes is ubiquitous, whereas the paternal silencing of UBE3A is confined to specific brain subregions; elsewhere it is bi-allelically expressed (56,57). Like the DLK1/GTL2 locus, the PWS/AS locus includes several clusters of small nucleolar RNAs (C/D box snoRNAs), but opposite to DLK1/GTL2, these snoRNAs are expressed exclusively from the paternal chromosome (58). Additionally, there is paternal-specific transcription of a very large, alternatively spliced antisense transcript (UBE3A-ATS), spanning ∼450 kb in human and ∼1 Mb in mice (59,60). Transcription of UBE3A-ATS emanates from promoters upstream of the SNURF/SNRPN transcription unit and extends through the UBE3A gene. Paternal expression and maternal repression of the genes in this region depends on a bipartite imprinting control region (ICR), delimited by microdeletions in PWS patients, spanning ∼100 kb upstream of SNRPN and including exon 1 of SNRPN (61,62). A deletion in mice covering 4.8 kb of DNA from within the first intron of Snrpn and upstream through its promoter confers ∼40% lethality when paternally transmitted, suggesting that critical elements of the ICR reside in this region (63). Mouse mutants abrogating the function of paternal-specific genes individually in the PWS region, however, were normal (Snurf/Snrpn) or had variably aberrant phenotypes (64–68). In total, the only mutation in mice that seems to recapitulate the severity of human PWS is the deletion of ∼42 kb of sequence corresponding to the microdeletion upstream of SNRPN in human PWS patients (69). No role as yet has been ascribed to the large UBE3A antisense transcripts in mice or humans, nor for the C/D box snoRNAs, although deletion of one set of snoRNAs (HBII-52) in humans has no apparent deleterious effect (70).
GNAS LOCUS
Transcription of genes at this relatively compact imprinted locus (human 20q13 and mouse distal 2) is exceptionally complex (Fig. 1F). Alternate transcripts emanating from four different allele-/tissue-specific promoters are spliced to a shared set of downstream exons (reviewed in 71). The core gene of this locus is GNAS, which is expressed ubiquitously and bi-allelically in all but a few tissues. It encodes Gsα, the α-subunit of the ubiquitous heterotrimeric G-protein complex, which mediates adenlyl cyclase activation by myriad different membrane receptors. Constitutive activating mutations in Gsα give rise to McCune–Albright syndrome, characterized variably by café-au-lait spots, gonadotropin-independent sexual precocity and fibrous dysplasia of bone (72,73). In certain hormone target tissues (renal proximal tubules, gonads and thyroid in humans and renal proximal tubule and brown and white adipose tissues in mice), GNAS is transcribed predominantly from the maternal allele (74,75). NESP55, encoding a chromogranin-like neuro-secretory protein, is also maternally expressed and emanates from a promoter ∼40 kb upstream of GNAS. Unusually, NESP55 incorporates into its 3′-untranslated region exons 2–13 of GNAS (76). Three paternal transcripts are also generated at this locus: XLαs (Gnasxl in mice), an alternate splice form of GNAS encoding a protein with a longer N-terminal extension; NESPAS, a non-coding, spliced antisense transcript to NESP55 and a non-coding, truncated GNAS transcript emanating from an upstream alternate promoter/exon 1A (also known as A/B) (77–79). Imprinted expression of the locus is governed by differential methylation of CpGs at four DMRs. The maternal chromosome is methylated at the exon 1A promoter, the XLαs promoter and the NESPAS promoter. The paternal chromosome is methylated only at the NESP55 promoter (80,81).
Mutations that inactivate Gsα in humans cause Albright hereditary osteodystrophy (AHO), characterized by short stature, obesity and subcutaneous ossifications (82,83). AHO patients inheriting the mutation from their mothers also exhibit pseudohypoparathyroidism 1A, displaying resistance to PTH, TSH and gonadotropins in target tissues (84,85). Epimutation, i.e. loss of maternal allele methylation at exon 1A, results in pseudohypoparathyroidism 1B (PHP1B) without AHO, presumably because activity is maintained in tissues where Gsα is bi-allelically expressed (86). Similarly, a deletion of exon 1A in the mouse Gnas locus abolishes tissue-specific paternal silencing of Gnas (87). Paternal transmission of this mutation is capable of rescuing PTH resistance in a maternally transmitted Gnas loss-of-function mutant. Mice inheriting a paternal deletion of Gnasxl, exhibit a spectrum of feeding and metabolic deficiencies (88). A recent report (89) implicates the NESP55 DMR and possibly the antisense transcript itself in transcriptional control of GNAS. Two kindreds presented with PHP1B resulting from maternally inherited deletions encompassing the entire NESP55 gene and exons 3 and 4 of NESPAS. Loss of methylation at both the XLαs and exon 1A DMRs was observed, abolishing Gsα expression in renal proximal tubules and leading to PTH resistance. Additionally, one individual was shown to express NESPAS inappropriately from the maternal allele (albeit missing exons 3 and 4) in lymphoblastoid cells. Although the control of imprinted expression at this locus remains poorly understood, the deletions in these two kindreds are suggestive of hierarchical regulation with the NESP55 DMR and NESPAS at the top. Paradoxically, differential methylation at the Gnasxl and exon 1A DMRs has been shown to be established during gametogenesis, yet methylation of paternal Nesp DMR in mice is not established until after implantation (80,81). It has been suggested that expression of Nespas in preimplantation stages may be instrumental in establishing the Nesp DMR imprint later in development (81), although expression of Nespas in early embryos has not yet been studied in detail.
XIST
Our best understanding of the role of non-coding RNAs in the silencing of mammalian genes is built upon studies of the role of Xist and its antagonistic antisense partner, Tsix, in achieving sex chromosome dosage compensation in mammals (Fig. 1G). XIST/Xist transcripts are expressed exclusively from the X-chromosome destined for inactivation (Xi), remain closely associated with it and propagate silencing in cis by physically coating it (90–92). The processed XIST/Xist transcript is relatively large (∼17 kb in humans and ∼15 kb in mice) and is comprised mostly unconstrained sequence with a few regions of high conservation (93–95). The exact nature of how Xist brings about X-inactivation is not fully understood, but the earliest events following the initiation or derepression (discussed subsequently) of Xist expression in preimplantation embryos involves the recruitment of heterochromatin assembly factors (96,97). There is a hierarchical progression of key factors from preimplantation stages, when silencing is more labile, to the establishment of stable heterochromatin covering much of Xi-inactivation in later stages (98). The exact nature and order of this progression remains somewhat controversial. At the earliest stages, Xist induced silencing is reversible and involves deacetylation of the core nucleosomal histones and selective methylation or demethylation of key lysine residues on histone H3 and H4. Evidence suggests that the recruitment by Xist of enzymes (e.g. histone deacetylases, SET domain proteins and Polycomb group proteins) responsible for these histone modifications is a critical step in initiation of silencing. Maintenance of silencing is Xist independent and involves epigenetic modifications, which can be propagated through replication cycles including hypoacetylation of histones, assembly of nucleosomes incorporating the histone variant MacroH2A1.2 and CpG methylation (recently reviewed in 99).
In mouse trophectoderm, X-inactivation is imprinted; the paternally derived X-chromosome is preferentially silenced (100), although this is not the case in humans (101). In mouse extraembryonic tissues, the maternal X is maintained as the active X (Xa) by the transcription of the non-coding, spliced antisense transcript, Tsix (102,103). The nature of the imprinting mark has remained elusive, but the 5′ end of the Tsix transcription unit harbors a CpG island and a cluster of repeats shown to attract CTCF binding (104). Slightly farther upstream of this CpG island is the element, DxPas34, which has been shown to exhibit differential methylation corresponding to X-activation, but apparently is not the imprinting mark (105). Indeed, deletion of the DNA methyltransferases Dnmt3a/Dnmt3b in mice, resulting in loss of virtually all de novo DNA methylation during embryonic development, has no effect on the proper mono-allelic expression of Xist (106). There is general agreement that random X-inactivation exhibited by the embryo proper is the result of re-activation of the paternal X in cells of the epiblast in late stage blastocysts, followed by a random choice mechanism (96–98). Paternal-specific expression of Xist initiates in early cleavage stages of the mouse embryo, but exactly when Xist transcripts coat and effect paternal X silencing is controversial (107). Deletion of the CpG island eliminates Tsix expression and biases the choice of Xi toward the deleted X in the embryo, suggesting that Tsix is critical in Xi choice (103). This deletion has no effect when inherited paternally, but results in up to 98% lethality in both males and females when maternally inherited because of inappropriate silencing of the maternal X in trophectoderm. Thus, it is clear that Tsix is a key regulator of Xist transcription. How Tsix interferes with Xist expression has been addressed in experiments by Shibata and Lee (108). Truncation of Tsix short of its overlap with Xist destroys its ability to silence Xist, suggesting that similar to Air, interaction of the Tsix RNA with its sense counterpart is essential to silencing.
CONSENSUS?
This review has offered only an abbreviated catalog of non-coding RNAs expressed from a few well-studied loci in mammals. Other imprinted loci, which did not receive mention, also exhibit non-coding and/or antisense transcripts (109,110). Can a mechanistic consensus be constructed from the various threads of research on these genes? A surfeit of caveats thwarts our attempts to apply neat mechanistic scenarios to even the best studied of these loci. For instance, the Air transcript is expressed in mouse embryonic brain, yet Igf2r is apparently expressed bi-allelically there (111). Similarly, X-inactivation occurs in spermatogenic cells in male mice, where Xist is actively transcribed but apparently is un-involved in X-linked gene silencing (112). Futhermore, paternal silencing of GNAS/Gnas relies on the activity of an overlapping sense non-coding transcript (87). These cases show that in at least certain circumstances, the action of these non-coding RNAs is neither sufficient nor necessary, nor necessarily antisense, to achieve gene silencing. A prominent question on the minds of researchers is whether the myriad non-coding and micro-RNA transcripts at imprinted loci mediate silencing through RNAi, an important promoter of heterochromatin formation in plants, fungi, worms and flies. RNAi can operate either by post-transcriptional destruction of double-strand RNA or by recruitment of heterochromatin assembly factors through the interfering RNAs themselves. Other mechanisms at the core of sense/antisense transcriptional interaction suggested, but as yet unproven, include enhancer/promoter occlusion or competition and counter-current RNA PolII obstruction. There is really nothing to suggest that each of these mechanisms might not be employed in one way or another at the many different loci exhibiting parent-of-origin specific expression in mammals. The complexities of epigenetic regulation at these loci indicate that natural selection has visited and re-visited them many times. If a genetic conflict lies at the evolutionary heart of genomic imprinting and there is ample evidence (113) to suggest this, then natural selection, being an opportunistic force, likely co-opted whatever regulatory mechanisms were at hand. That we are around to ponder it suggests that a lack of consensus may not be such a bad thing.
ACKNOWLEDGEMENTS
The author would like to express deepest gratitude to Rachel O'Neill for illustrations and for critical reading of the manuscript. The author would also like to thank two anonymous reviewers for helpful comments.
Locus . | Non-coding RNA . | Expressed parental allele . | Silencing targets . |
---|---|---|---|
Igf2/H19 | H19 | Maternal | None |
Igf2r | Air | Paternal | Igf2r |
Slc22a2 | |||
Slc22a3 | |||
Kcnq1 | Kcnq1ot | Paternal | Unknown |
Dlk/Gtl2 | Anti-Rtl1 (mir127 and mir136) | Maternal | Unknown |
C/D snoRNA genes | Maternal | ||
miRNA genes and Mrg | Maternal | ||
Anti-Dio3 | Maternal | ||
PWS/AS | Ube3a-ats and snoRNA genes | Paternal | Ube3a |
Gnas | Nespas | Paternal | Nesp |
1A | Paternal | Gsα | |
Xist | Xist | Paternal* | X chr in cis |
Tsix | Maternal* | Xist |
Locus . | Non-coding RNA . | Expressed parental allele . | Silencing targets . |
---|---|---|---|
Igf2/H19 | H19 | Maternal | None |
Igf2r | Air | Paternal | Igf2r |
Slc22a2 | |||
Slc22a3 | |||
Kcnq1 | Kcnq1ot | Paternal | Unknown |
Dlk/Gtl2 | Anti-Rtl1 (mir127 and mir136) | Maternal | Unknown |
C/D snoRNA genes | Maternal | ||
miRNA genes and Mrg | Maternal | ||
Anti-Dio3 | Maternal | ||
PWS/AS | Ube3a-ats and snoRNA genes | Paternal | Ube3a |
Gnas | Nespas | Paternal | Nesp |
1A | Paternal | Gsα | |
Xist | Xist | Paternal* | X chr in cis |
Tsix | Maternal* | Xist |
Asterisk denotes imprinted expression of Xist and Tsix in mouse extraembryonic tissues; expression is random/mono-allelic in the embryo proper.
Locus . | Non-coding RNA . | Expressed parental allele . | Silencing targets . |
---|---|---|---|
Igf2/H19 | H19 | Maternal | None |
Igf2r | Air | Paternal | Igf2r |
Slc22a2 | |||
Slc22a3 | |||
Kcnq1 | Kcnq1ot | Paternal | Unknown |
Dlk/Gtl2 | Anti-Rtl1 (mir127 and mir136) | Maternal | Unknown |
C/D snoRNA genes | Maternal | ||
miRNA genes and Mrg | Maternal | ||
Anti-Dio3 | Maternal | ||
PWS/AS | Ube3a-ats and snoRNA genes | Paternal | Ube3a |
Gnas | Nespas | Paternal | Nesp |
1A | Paternal | Gsα | |
Xist | Xist | Paternal* | X chr in cis |
Tsix | Maternal* | Xist |
Locus . | Non-coding RNA . | Expressed parental allele . | Silencing targets . |
---|---|---|---|
Igf2/H19 | H19 | Maternal | None |
Igf2r | Air | Paternal | Igf2r |
Slc22a2 | |||
Slc22a3 | |||
Kcnq1 | Kcnq1ot | Paternal | Unknown |
Dlk/Gtl2 | Anti-Rtl1 (mir127 and mir136) | Maternal | Unknown |
C/D snoRNA genes | Maternal | ||
miRNA genes and Mrg | Maternal | ||
Anti-Dio3 | Maternal | ||
PWS/AS | Ube3a-ats and snoRNA genes | Paternal | Ube3a |
Gnas | Nespas | Paternal | Nesp |
1A | Paternal | Gsα | |
Xist | Xist | Paternal* | X chr in cis |
Tsix | Maternal* | Xist |
Asterisk denotes imprinted expression of Xist and Tsix in mouse extraembryonic tissues; expression is random/mono-allelic in the embryo proper.
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