Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice

Canzio, Daniele; Nwakeze, Chiamaka L.; Horta, Adan; Rajkumar, Sandy M.; Coffey, Eliot L.; Duffy, Erin E.; Duffié, Rachel; Monahan, Kevin D.; O’Keeffe, Sean; Simon, Matthew D.; Lomvardas, Stavros; Maniatis, Tom

doi:10.1016/j.cell.2019.03.008

Cited by 156 publications

(165 citation statements)

References 50 publications

(72 reference statements)

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“…In both endogenous and engineered systems, infrequent chromosomal contacts can lead to gene activation, perhaps by facilitating the assembly of TFs (Apostolou and Thanos, 2008). The stochasticity of these contacts might mediate the stochastic or monoallelic activation of a promoter (Canzio et al, 2019;Guo et al, 2012;Monahan et al, 2019). However, a functional role for 3D genome organization in this context is speculative, and establishing causality remains challenging.…”

Section: Biophysics Of Tf Activitymentioning

confidence: 99%

Mechanisms of Interplay between Transcription Factors and the 3D Genome

2019

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Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby serve as the protein anchors and determinants of 3D genome organization. Conversely, chromatin conformation shapes TF activity, for example by looping TF-bound enhancers to distally located target genes. Despite considerable effort, our understanding of the mechanistic relationship between TFs and 3D genome organization remains limited, in large part due to this interdependency. In this review, we summarize the evidence for the diverse mechanisms by which TFs and their activity shape the 3D genome, and vice versa. We further highlight outstanding questions and potential approaches for untangling the complex relationship between TF activity and the 3D genome.

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Section: Biophysics Of Tf Activitymentioning

confidence: 99%

Mechanisms of Interplay between Transcription Factors and the 3D Genome

2019

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“…ong non-coding RNAs (lncRNAs) are defined as a class of RNAs whose transcripts are >200 nucleotides (nt) without open reading frame or protein-coding potential. After microRNAs (miRNAs), lncRNAs are rapidly emerging as important ncRNA, which have been proved to be distinctly involved in a wide range of biological and cellular processes in development and disease [1][2][3] . Compared with protein-coding RNAs, lncRNAs are often modest evolutionary conservation, unstable, relatively lower abundance in vivo, and tighter tissuespecific expression, which result in difficulties in lncRNAs research 4,5 .…”

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confidence: 99%

NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death

Liu

Zhang

et al. 2020

Commun Biol

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Long intergenic non-coding RNAs (lincRNAs) have been proved to be involved in regulating female reproduction. However, to what extent lincRNAs are involved in ovarian functions and fertility is incompletely understood. Here we show that a lincRNA, NORFA is involved in granulosa cell apoptosis, follicular atresia and sow fertility. We found that NORFA was downregulated during follicular atresia, and inhibited granulosa cell apoptosis. NORFA directly interacted with miR-126 and thereby preventing it from binding to TGFBR2 3′-UTR. miR-126 enhanced granulosa cell apoptosis by attenuating NORFA-induced TGF-β signaling pathway. Importantly, a breed-specific 19-bp duplication was detected in NORFA promoter, which proved association with sow fertility through enhancing transcription activity of NORFA by recruiting transcription factor NFIX. In summary, our findings identified a candidate lincRNA for sow prolificacy, and provided insights into the mechanism of follicular atresia and female fertility.

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“…While increases in apparent CTCF-binding to the non-CBE-containing RC upon CTCF depletion could be considered surprising, it may likely occur indirectly due to cohesin-mediated loop extrusion-driven dynamic associations of the RC sub-loop anchor with residual-CTCF-bound CBEs across Igh. The, apparently, uneven depletion of CTCF at various CBEs may reflect differential intrinsic CTCF-binding affinity, local chromatin context and/or other factors [43][44][45] . Upon CTCF depletion, Rad21 occupancy throughout Igh was also greatly diminished, with residual binding sites and levels largely reflecting those of CTCF ( Fig.…”

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confidence: 99%

CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning

Lou

Dring

et al. 2020

Preprint

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RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells 1 . Upon binding a recombination center (RC)-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin 2-10 , to locate Ds and assemble a DJH-based RC 11 . CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning 12-15 ; but their inactivation allows scanning to proximal VHs where additional CBEs activate rearrangement and impede scanning any further upstream 15,16 . Distal VH utilization is thought to involve diffusional RC access following large-scale Igh locus contraction 17-23 . Here, we test the potential of linear RAG-scanning to mediate distal VH usage in G1-arrested, v-Abl-pro-B cell lines 24,25 , which undergo robust D-to-JH but little VH-to-DJH rearrangements, presumably due to lack of locus contraction 11,15 . Through an auxin-inducible approach 26,27 , we degrade the cohesin-component Rad21 4,7,27 or CTCF 7,9 in these G1-arrested lines, which maintain substantial viability throughout four-day experiments. Rad21 degradation eliminated all V(D)J recombination and RAG-scanning-associated interactions, except RC-located DQ52-to-JH joining in which synapsis occurs by diffusion 11 . Remarkably, while CTCF degradation suppressed most CBE-based chromatin interactions, it promoted robust RC interactions with, and robust VH-to-DJH joining of, distal VHs, with patterns similar to those of "locus-contracted" primary pro-B cells. Thus, downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG-scanning across the 2.7Mb Igh locus.Cohesin is a highly conserved chromosome-associated multi-subunit ring-shaped ATPase complex built upon subunits belonging to the structural maintenance of chromosomes (Smc) family and is important for diverse chromosome-based processes [28][29][30][31][32][33] .The cohesin complex is proposed to form contact loop domains by extrusion of chromatin until reaching convergent CTCF-bound CBE anchors 2-10 . In this regard, cohesin extrudes both naked and nucleosome-containing DNA in an NIPBL-MAU2 and ATP-hydrolysisdependent manner in vitro 34,35 . Our studies implicated the cohesin complex in chromatin loop extrusion-mediated mechanisms of lymphocyte V(D)J and IgH class switch recombination 11,[14][15][16]36,37 . To further elucidate potential cohesin role(s) in chromatin scanning during long-range V(D)J recombination, we employed a mini auxin-inducible degron (mAID) approach 4,7,26,27 to conditionally degrade Rad21, a core component of the cohesin complex,in v-Abl-kinase-transformed, Eµ-Bcl2-expressing mouse pro-B cells ("v-Abl pro-B cells").

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Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice

Cited by 156 publications

References 50 publications

Mechanisms of Interplay between Transcription Factors and the 3D Genome

Mechanisms of Interplay between Transcription Factors and the 3D Genome

NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death

CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning

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