An expansive human regulatory lexicon encoded in transcription factor footprints

Neph, Shane; Vierstra, Jeff; Stergachis, Andrew B.; Reynolds, Alex; Haugen, Eric; Vernot, Benjamin; Thurman, Robert E.; John, Sam; Sandstrom, Richard; Johnson, Audra; Maurano, Matthew T.; Humbert, Richard; Rynes, Eric; Wang, Hao; Vong, Shinny; Lee, Kristen; Bates, Daniel; Diegel, Morgan; Roach, Vaughn; Dunn, Douglas; Neri, Jun; Schafer, Anthony; Hansen, R. Scott; Kutyavin, Tanya; Giste, Erika; Weaver, Molly; Canfield, Theresa K.; Sabo, Peter J.; Zhang, Miaohua; Balasundaram, Gayathri; Byron, Rachel; MacCoss, Michael J.; Akey, Joshua M.; Bender, Michael A.; Groudine, Mark; Kaul, Rajinder; Stamatoyannopoulos, J

doi:10.1038/nature11212

Cited by 722 publications

(834 citation statements)

References 45 publications

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“…ENCODE ChIP‐seq data and our ChIP experiment point out RXRA as a direct regulator of ITPR2 , although the identified RXRA binding site does not contain AGGTCA sequences which are the most frequent RXRA binding motifs (Evans, & Mangelsdorf, 2014; Sever, & Glass, 2013) and is located in the second intron of ITPR2 rather than in its promoter. However, modulation of gene expression through the binding of transcriptional regulators in introns is more and more documented (Neph et al, 2012). Our work is the first to link RXRA with calcium signaling.…”

Section: Discussionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting 160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family, represses ITPR2 expression and regulates calcium signaling though ITPR2 and the mitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53, whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors.

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Section: Discussionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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“…To identify cis-elements, we performed de novo motif identification around the branchpoint (Neph et al 2012). This resolved a set of 5-to 6-nt sequence motifs that overlap ;53% of all branchpoint annotations and can undergo base-pairing interactions with the U2 snRNA ( Fig.…”

Section: Branchpoint Motifsmentioning

confidence: 99%

Genome-wide discovery of human splicing branchpoints

et al. 2015

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During the splicing reaction, the 59 intron end is joined to the branchpoint nucleotide, selecting the next exon to incorporate into the mature RNA and forming an intron lariat, which is excised. Despite a critical role in gene splicing, the locations and features of human splicing branchpoints are largely unknown. We use exoribonuclease digestion and targeted RNA-sequencing to enrich for sequences that traverse the lariat junction and, by split and inverted alignment, reveal the branchpoint. We identify 59,359 high-confidence human branchpoints in >10,000 genes, providing a first map of splicing branchpoints in the human genome. Branchpoints are predominantly adenosine, highly conserved, and closely distributed to the 39 splice site. Analysis of human branchpoints reveals numerous novel features, including distinct features of branchpoints for alternatively spliced exons and a family of conserved sequence motifs overlapping branchpoints we term B-boxes, which exhibit maximal nucleotide diversity while maintaining interactions with the keto-rich U2 snRNA. Different B-box motifs exhibit divergent usage in vertebrate lineages and associate with other splicing elements and distinct intron-exon architectures, suggesting integration within a broader regulatory splicing code. Lastly, although branchpoints are refractory to common mutational processes and genetic variation, mutations occurring at branchpoint nucleotides are enriched for disease associations.[Supplemental material is available for this article.]The majority of human genes are spliced, a process whereby introns are removed from the nascent RNA and the remaining exonic sequence joined together into a mature RNA transcript. In addition, alternative splicing generates complex networks of isoforms from human gene loci and plays a major role in shaping the diversity of the transcriptome (Kapranov et al. 2005;Gerstein et al. 2007;Djebali et al. 2012).Splicing occurs in the spliceosome, a large ribonucleoprotein complex that recognizes at least three genetic elements within each intron: the 59 splice site (59SS), the 39 splice site (39SS), and the branchpoint (Will and L€ uhrmann 2011). RNU2-1, the U2 spliceosomal RNA (snRNA) base pairs to the sequence surrounding the unpaired branchpoint nucleotide, which then undergoes transesterification with the 59 end of the intron to form a closed lariat structure. The spliceosome then scans for the downstream 39 splice site, which undergoes a second trans-esterification reaction to join together the two exon ends and excise the intron lariat (Fig.

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“…The WGATAR motifs and intervening sequence that were removed by homologous recombination are indicated. (B) ChIPsequencing profiles for factor occupancy and histone modifications at the Gata2 locus mined from existing datasets (37,(69)(70)(71)(72). BM, bone marrow; H3K27a, acetylation of H3 at lysine 27; H3K4m1, monomethylation of histone H3 at lysine 4; MEL, murine erythroleukemia cells.…”

Section: Significancementioning

confidence: 99%

Mechanism governing a stem cell-generating cis -regulatory element

Sanalkumar

Johnson

Gào

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The unremitting demand to replenish differentiated cells in tissues requires efficient mechanisms to generate and regulate stem and progenitor cells. Although master regulatory transcription factors, including GATA binding protein-2 (GATA-2), have crucial roles in these mechanisms, how such factors are controlled in developmentally dynamic systems is poorly understood. Previously, we described five dispersed Gata2 locus sequences, termed the −77, −3.9, −2.8, −1.8, and +9.5 GATA switch sites, which contain evolutionarily conserved GATA motifs occupied by GATA-2 and GATA-1 in hematopoietic precursors and erythroid cells, respectively. Despite common attributes of transcriptional enhancers, targeted deletions of the −2.8, −1.8, and +9.5 sites revealed distinct and unpredictable contributions to Gata2 expression and hematopoiesis. Herein, we describe the targeted deletion of the −3.9 site and mechanistically compare the −3.9 site with other GATA switch sites. The −3.9 −/− mice were viable and exhibited normal Gata2 expression and steady-state hematopoiesis in the embryo and adult. We established a Gata2 repression/reactivation assay, which revealed unique +9.5 site activity to mediate GATA factor-dependent chromatin structural transitions. Loss-of-function analyses provided evidence for a mechanism in which a mediator of long-range transcriptional control [LIM domain binding 1 (LDB1)] and a chromatin remodeler [Brahma related gene 1 (BRG1)] synergize through the +9.5 site, conferring expression of GATA-2, which is known to promote the genesis and survival of hematopoietic stem cells.cis element | HSCs W hereas proximal promoter sequences assemble the basal transcriptional machinery and RNA polymerase, distant cis-regulatory elements often confer tissue-specific or contextdependent transcriptional regulation. Enhancer elements reside many kilobases upstream or downstream of a promoter or within introns, and extensive efforts have focused on elucidating "action-at-a-distance" mechanisms (1). Long-range transcriptional control involves physical interactions between proteins bound at distal regions and promoter sequences and higher order structural transitions, including subnuclear relocalization of target loci (2-4). Given the high frequency of long-range mechanisms at mammalian loci and the mutations that disrupt the function of such elements in pathological conditions, elucidating the underlying mechanisms in development,

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An expansive human regulatory lexicon encoded in transcription factor footprints

Cited by 722 publications

References 45 publications

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Genome-wide discovery of human splicing branchpoints

Mechanism governing a stem cell-generating cis -regulatory element

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