Rich The Factor - Leaving It All On The Field.rar
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Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Considered to have intrinsic transcriptional activity, have some natural ligands such as all-trans retinoic acid (ATRA) and other retinoids which act as inverse agonists repressing the transcriptional activity. Required for normal postnatal development of rod and cone photoreceptor cells. Modulates rod photoreceptors differentiation at least by inducing the transcription factor NRL-mediated pathway. In cone photoreceptor cells, regulates transcription of OPN1SW. Involved in the regulation of the period length and stability of the circadian rhythm. May control cytoarchitectural patterning of neocortical neurons during development. May act in a dose-dependent manner to regulate barrel formation upon innervation of layer IV neurons by thalamocortical axons. May play a role in the suppression of osteoblastic differentiation through the inhibition of RUNX2 transcriptional activity (By similarity). (RORB_HUMAN,Q92753 )
Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-α (PML/RARα), generated by the chromosome translocation t(15;17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here, we provide rich evidence of how PML/RARα drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RARα is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, 2 widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RARα-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RARα, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RARα on chromatin in coregulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.
a Histone-modifying genes of interest (KMT2C, KMT2D, EHMT1, KDM6A, CRBBP, and EP300) functional domains scale schematic. Amino acids (aa), Plant homeodomain (PHD), high mobility group domain (HMG), F/Y-rich N-terminus domain (FYRN), F/Y-rich C-terminus domain (FYRC), SET domain (SET), post-SET domain (POST), pre-SET domain (PRE), Ankyrin repeat domain (ANK), JmjC domain (JmjC), tetratricopeptide repeat protein domain (TPR), transcriptional adapter zinc binding domain (TAZ), kinase-inducible domain interacting domain (KIX), bromodomain (BROMO), histone acetyltransferase domain (HAT). b Schematic of KCDCOM. COMPASS-like complexes (KCDCOMs, also historically known as ASC2-binding complexes, ASCOMs) bind multiple unique subunits (NCOA6/ASC2, KDM6A/UTX, PTIP, and PAGR1/PA1) and interact with chromatin via histone tail post-translational modifications and DNA binding cofactors. RA retinoic acid. WRAD WDR5 (WD repeat domain 5), RBBP5 (retinoblastoma binding protein 5), ASHL2 (absent, small or homeotic 2-like), and DPY-30 (Dumpy-30)
In order to study the functional role of KMT2C in neurons and thus infer how KMT2C mutations may be implicated in the intellectual disability syndrome phenotype, studies were conducted in Drosophila trr, which shares a one-to-two evolutionary relationship with human orthologs KMT2C and KMT2D. Because homozygous mutations in trr are lethal, a Gal4/UAS system and inducible RNA interference (RNAi) system were employed to ascertain the role of trr in the adult fly nervous system. Studies indicated that trr is localized in the nuclei of the mushroom body calyx (structures in fly brain required for olfactory learning and memory). Though flies with trr knockdown had no gross morphologic defects in the mushroom body, they did demonstrate abnormal courtship conditioning memory (a classic and well-studied behavior paradigm), which indicates a defect in learning and memory. Chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) studies of wild-type Drosophila heads with antibody to trr revealed genomic regions that were highly enriched for trr binding. Analysis of these regions indicated that approximately 75% of trr binding sites were located within 1 kb upstream or downstream of transcription start sites (tss) of 2362 unique genes and that approximately 25% of trr binding sites were associated with other genomic features, such as low-complexity regions or transcription termination sites. These findings are consistent with the roles of KMT2C and KMT2D in transcriptional activation [70, 123].
Epping and colleagues demonstrated that over-expressed TAP-tagged PRAME can be co-immunoprecipitated with RARα, with the interaction being dependent on the C-terminus of PRAME [8]. Weak direct interactions of PRAME and RARα in GST-pulldown experiments were reported, whereas no binding of PRAME to ER or RXR was detected [8]. Due to its leucine-rich content, PRAME contains at least seven sequences matching the consensus of the LXXLL signature motif found in many nuclear receptor binding proteins [49]. However, only one of these (i.e., 467-L RELL CE-473, located close to the C-terminus of PRAME) was found to contribute to interactions with the RARα LBD in vitro [8]. Unlike most other LXXLL motif containing cofactors, the interaction of PRAME with RARα was not reported to be dependent on ligand. Moreover, mutations in the RARα AF2 helix, which is essential to generate the LXXLL peptide binding surface, did not alter the ability of PRAME to repress RA signalling [48]. 59ce067264
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