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ABSTRACT: The molecular basis underlying the physiologically well-defined orexigenic function of glucocorticoid (Gc) is unclear. Brain-specific homeobox factor (Bsx) is a positive regulator of the orexigenic neuropeptide, agouti-related peptide (AgRP), in AgRP-neurons of the hypothalamic arcuate nucleus. Here we show that, in response to fasting-elevated Gc levels, Gc receptor (GR) and Bsx synergize to direct activation of AgRP transcription. This synergy is dictated by unique sequence features in a novel Gc response element in AgRP (AgRP-GRE). In contrast to AgRP-GRE, Bsx suppresses transactivation directed by many conventional GREs, functioning as a gene context-dependent modulator of GR actions or a target selector for GR. Consistently, AgRP-GRE drives fasting-dependent activation of a target gene specifically in GR(+)Bsx(+) AgRP-neurons. These results define AgRP as a common orexigenic target gene of GR and Bsx, and provide an opportunity to identify their additional common targets, facilitating our understanding of the molecular basis underlying the orexigenic activity of Gc and Bsx.
Molecular and cellular biology 05/2013; · 6.06 Impact Factor
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ABSTRACT: Combinatorial transcription codes generate the myriad of cell types during development and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIM-complex mimicking fusion, induces a signature of MN transcriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM domain of Lhx3 are crucial for generating MNs without up-regulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of Isl1 and Lhx3 and the LIM domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog (Shh). RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of using embryonic transcription complexes for producing specific cell types from stem cells.
Proceedings of the National Academy of Sciences 02/2012; 109(9):3383-8. · 9.68 Impact Factor
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ABSTRACT: The removal of histone H3 lysine27 (H3K27) trimethylation mark is important for the robust induction of many cell type-specific genes during differentiation. Here we show that UTX, a H3K27 demethylase, acts as a critical switch to promote a cardiac-specific gene program. UTX-deficient ESCs failed to develop heart-like rhythmic contractions under a cardiac differentiation condition. UTX-deficient mice show severe defects in heart development and embryonic lethality. We found that UTX is recruited to cardiac-specific enhancers by associating with core cardiac transcription factors and demethylates H3K27 residues in cardiac genes. In addition, UTX facilitates the recruitment of Brg1 to the cardiac-specific enhancers. Together, our data reveal key roles for UTX in a timely transition from poised to active chromatin in cardiac genes during heart development and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes.
Developmental cell 12/2011; 22(1):25-37. · 13.36 Impact Factor
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ABSTRACT: The development of the central nervous system (CNS) is governed by networks of extrinsic and intrinsic molecular programs that together orchestrate precise gene regulation. For the past few years, significant progress has been made in the characterization of histone-modifying enzymes and the roles they play in transcriptional control by affecting chromatin structure. Importantly, recent studies have revealed dynamic changes in histone modifications over the course of neural cell-fate specification. Further understanding of physiological functions of histone-modifying enzymes and their molecular mechanisms of action in CNS development will provide crucial insights into the process of generating neural cell types with tremendous diversity. Here we discuss the recent advancement in understanding the roles of enzymes involved in histone acetylation and methylation during neural cell-type specification.
Current opinion in neurobiology 02/2010; 20(1):29-36. · 7.21 Impact Factor
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ABSTRACT: Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralog p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin.
Neuron 07/2009; 62(5):641-54. · 14.74 Impact Factor
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ABSTRACT: ASC-2, a multifunctional coactivator, forms a steady-state complex, named ASCOM (for ASC-2 COMplex), that contains the histone H3-lysine-4 (H3K4)-methyltransferase MLL3 or its paralogue MLL4. Somewhat surprisingly, given prior indications of redundancy between MLL3 and MLL4, targeted inactivation of the MLL3 H3K4-methylation activity in mice is found to result in ureter epithelial tumors. Interestingly, this phenotype is exacerbated in a p53(+/-) background and the tumorigenic cells are heavily immunostained for gammaH2AX, indicating a contribution of MLL3 to the DNA damage response pathway through p53. Consistent with the in vivo observations, and the demonstration of a direct interaction between p53 and ASCOM, cell-based assays have revealed that ASCOM, through ASC-2 and MLL3/4, acts as a p53 coactivator and is required for H3K4-trimethyation and expression of endogenous p53-target genes in response to the DNA damaging agent doxorubicin. In support of redundant functions for MLL3 and MLL4 for some events, siRNA-mediated down-regulation of both MLL3 and MLL4 is required to suppress doxorubicin-inducible expression of several p53-target genes. Importantly, this study identifies a specific H3K4 methytransferase complex, ASCOM, as a physiologically relevant coactivator for p53 and implicates ASCOM in the p53 tumor suppression pathway in vivo.
Proceedings of the National Academy of Sciences 06/2009; 106(21):8513-8. · 9.68 Impact Factor
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ABSTRACT: Multiple excitatory and inhibitory interneurons form the motor circuit with motor neurons in the ventral spinal cord. Notch signaling initiates the diversification of immature V2-interneurons into excitatory V2a-interneurons and inhibitory V2b-interneurons. Here, we provide a transcriptional regulatory mechanism underlying their balanced production. LIM-only protein LMO4 controls this binary cell fate choice by regulating the activity of V2a- and V2b-specific LIM complexes inversely. In the spinal cord, LMO4 induces GABAergic V2b-interneurons in collaboration with SCL and inhibits Lhx3 from generating glutamatergic V2a-interneuons. In LMO4;SCL compound mutant embryos, V2a-interneurons increase markedly at the expense of V2b-interneurons. We further demonstrate that LMO4 nucleates the assembly of a novel LIM-complex containing SCL, Gata2, and NLI. This complex activates specific enhancers in V2b-genes consisting of binding sites for SCL and Gata2, thereby promoting V2b-interneuron fate. Thus, LMO4 plays essential roles in directing a balanced generation of inhibitory and excitatory neurons in the ventral spinal cord.
Neuron 04/2009; 61(6):839-51. · 14.74 Impact Factor
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ABSTRACT: Nuclear receptor (NR) transactivation involves multiple coactivators, and the molecular basis for how these are functionally integrated needs to be determined to fully understand the NR action. Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of many NRs and transcription factors, forms a steady-state complex, ASCOM (for ASC-2 complex), which contains histone H3-lysine-4 (H3K4) methyltransferase MLL3 or its paralog MLL4. Here, we show that ASCOM requires a functional cross talk with the ATPase-dependent chromatin remodeling complex Swi/Snf for efficient NR transactivation. Our results reveal that ASCOM and Swi/Snf are tightly colocalized in the nucleus and that ASCOM and Swi/Snf promote each other's binding to NR target genes. We further show that the C-terminal SET domain of MLL3 and MLL4 directly interacts with INI1, an integral subunit of Swi/Snf. Our mutational analysis demonstrates that this interaction underlies the mutual facilitation of ASCOM and Swi/Snf recruitment to NR target genes. Importantly, this study uncovers a specific protein-protein interaction as a novel venue to couple two distinct enzymatic coactivator complexes during NR transactivation.
Molecular Endocrinology 03/2009; 23(5):610-9. · 4.54 Impact Factor
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ABSTRACT: Activating signal cointegrator-2 (ASC-2), a transcriptional coactivator of multiple transcription factors that include the adipogenic factors peroxisome proliferator-activated receptor gamma (PPARgamma) and C/EBPalpha, is associated with histone H3-Lys-4-methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a complex named ASCOM (ASC-2 complex). Indeed, ASC-2-null mouse embryonic fibroblasts (MEFs) have been demonstrated to be refractory to PPARgamma-stimulated adipogenesis and fail to express the PPARgamma-responsive adipogenic marker gene aP2. However, the specific roles for MLL3 and MLL4 in adipogenesis remain undefined. Here, we provide evidence that MLL3 plays crucial roles in adipogenesis. First, MLL3(Delta/Delta) mice expressing a H3K4MT-inactivated mutant of MLL3 have significantly less white fat. Second, MLL3(Delta/Delta) MEFs are mildly but consistently less responsive to inducers of adipogenesis than WT MEFs. Third, ASC-2, MLL3, and MLL4 are recruited to the PPARgamma-activated aP2 gene during adipogenesis, and PPARgamma is shown to interact directly with the purified ASCOM. Moreover, although H3K4 methylation of aP2 is readily induced in WT MEFs, it is not induced in ASC-2(-/-) MEFs and only partially induced in MLL3(Delta/Delta) MEFs. These results suggest that ASCOM-MLL3 and ASCOM-MLL4 likely function as crucial but redundant H3K4MT complexes for PPARgamma-dependent adipogenesis.
Proceedings of the National Academy of Sciences 01/2009; 105(49):19229-34. · 9.68 Impact Factor
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ABSTRACT: Transcriptional regulation by nuclear hormone receptors (NRs) requires multiple coregulators that modulate chromatin structures by catalyzing a diverse array of posttranslational modifications of histones. Different combinations of these modifications yield dynamic functional outcomes, constituting an epigenetic histone code. This code is inscribed by histone-modifying enzymes and decoded by effector proteins that recognize specific covalent marks. One important modification associated with active chromatin structures is methylation of histone H3-lysine 4 (H3K4). Crucial roles for this modification in NR transactivation have been recently highlighted through our purification and subsequent characterization of a steady-state complex associated with ASC-2, a coactivator of NRs and other transcription factors. This complex, designated ASCOM for ASC-2 complex, contains H3K4-methyltransferase MLL3/HALR or its paralogue MLL4/ALR and represents the first Set1-like H3K4-methyltransferase complex to be reported in vertebrates. This review focuses on recent progress in our understanding of how ASCOM-MLL3 and ASCOM-MLL4 influence NR-mediated gene transcription and of their physiological function.
Progress in molecular biology and translational science 01/2009; 87:343-82.
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ABSTRACT: Spinal motor neurons (MNs) and V2 interneurons (V2-INs) are specified by two related LIM-complexes, MN-hexamer and V2-tetramer, respectively. Here we show how multiple parallel and complementary feedback loops are integrated to assign these two cell fates accurately. While MN-hexamer response elements (REs) are specific to MN-hexamer, V2-tetramer-REs can bind both LIM-complexes. In embryonic MNs, however, two factors cooperatively suppress the aberrant activation of V2-tetramer-REs. First, LMO4 blocks V2-tetramer assembly. Second, MN-hexamer induces a repressor, Hb9, which binds V2-tetramer-REs and suppresses their activation. V2-INs use a similar approach; V2-tetramer induces a repressor, Chx10, which binds MN-hexamer-REs and blocks their activation. Thus, our study uncovers a regulatory network to segregate related cell fates, which involves reciprocal feedforward gene regulatory loops.
Developmental cell 07/2008; 14(6):877-89. · 13.36 Impact Factor
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ABSTRACT: Activating signal cointegrator-2 (ASC-2), a coactivator of multiple nuclear receptors and transcription factors, including the liver X receptors (LXRs), is associated with histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) MLL3 or its paralogue MLL4 in a steady-state complex named ASCOM (ASC-2 complex). ASCOM belongs to Set1-like complexes, a conserved family of related H3K4MT complexes. ASC-2 binds to many nuclear receptors in a ligand-dependent manner through its two LXXLL motifs. In particular, the second motif has been shown to specifically recognize LXRs. However, the exact role for neither ASC-2 nor MLL3/4 in LXR transactivation is clearly defined. Here, we show that the key function of ASC-2 in transactivation by LXRs is to present MLL3 and MLL4 to LXRs. Thus, ASC-2 is required for ligand-induced recruitment of MLL3 and MLL4 to LXRs, and LXR ligand T1317 induces not only expression of LXR-target genes but also their H3K4-trimethylation. Strikingly, both of these ligand effects are ablated in ASC-2-null cells but only partially suppressed in cells expressing an enzymatically inactivated mutant MLL3. Our results also reveal that transactivation by LXRs does not appear to require other Set1-like complexes. Taken together, these results suggest that ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in ligand-dependent H3K4 trimethylation and expression of LXR-target genes, and that ASC-2 is likely a key determinant for LXRs to function through ASCOM but not other Set1-like complexes.
Molecular Endocrinology 07/2008; 22(6):1312-9. · 4.54 Impact Factor
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ABSTRACT: Neuronal gene expression is tightly regulated in developing CNS. Here, we demonstrate the anti-neural function of phosphatase SCP1 (small C-terminal domain phosphatase 1) during development. We further show that the neuron-enriched microRNA miR-124 directly targets SCP1-3' untranslated region (UTR) to suppress SCP1 expression. In developing spinal cord, expression of miR-124 and SCP1 is complementary, and miR-124 antagonism phenocopies SCP1 overexpression and vice versa. In P19 cells, miR-124 suppresses SCP1 expression and induces neurogenesis, and SCP1 counteracts this proneural activity of miR-124. Our results suggest that, during CNS development, timely down-regulation of SCP1 is critical for inducing neurogenesis, and miR-124 contributes to this process at least in part by down-regulating SCP1 expression.
Genes & Development 04/2007; 21(7):744-9. · 11.66 Impact Factor
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ABSTRACT: Activating signal cointegrator-2 (ASC-2), a coactivator of multiple transcription factors that include retinoic acid receptor (RAR), associates with histone H3-K4 methyltranferases (H3K4MTs) MLL3 and MLL4 in mixed-lineage leukemia. Here, we show that mice expressing a SET domain mutant of MLL3 share phenotypes with isogenic ASC2+/- mice and that expression and H3-K4 trimethylation of RAR target gene RAR-beta2 are impaired in ASC-2-null mouse embryo fibroblasts (MEFs) or in MEFs expressing siRNAs against both MLL3 and MLL4. We also show that MLL3 and MLL4 are found in distinct ASC-2-containing complexes rather than in a common ASC-2 complex, and they are recruited to RAR-beta2 by ASC-2. In contrast, RAR-beta2 expression is intact in MEFs devoid of menin, a component of MLL1 and MLL2 H3K4MT complexes. These results suggest that ASC-2 confers target gene specificity to MLL3 and MLL4 H3K4MT complexes and that recruitment of H3K4MTs to their target genes generally involves interactions between integral components of H3K4MT complexes and transcription factors.
Proceedings of the National Academy of Sciences 11/2006; 103(42):15392-7. · 9.68 Impact Factor
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ABSTRACT: Histone H3 Lys4 (H3K4) methylation is a prevalent mark associated with transcription activation. A common feature of several H3K4 methyltransferase complexes is the presence of three structural components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Here we report the first biochemical reconstitution of a functional four-component mixed-lineage leukemia protein-1 (MLL1) core complex. This reconstitution, combined with in vivo assays, allows direct analysis of the contribution of each component to MLL1 enzymatic activity and their roles in transcriptional regulation. Moreover, taking clues from a crystal structure analysis, we demonstrate that WDR5 mediates interactions of the MLL1 catalytic unit both with the common structural platform and with the histone substrate. Mechanistic insights gained from this study can be generalized to the whole family of SET1-like histone methyltransferases in mammals.
Nature Structural & Molecular Biology 09/2006; 13(8):713-9. · 12.71 Impact Factor
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ABSTRACT: Activating signal cointegrator-2 (ASC-2) is a recently isolated transcriptional coactivator protein for a variety of different transcription factors, including many members of the nuclear receptor superfamily. In this report, we demonstrate that ASC-2 also serves as a coactivator of the xenobiotic nuclear receptor constitutive androstane receptor (CAR). First, transcriptional activation by CAR was enhanced by cotransfected ASC-2 in CV-1 and HeLa cells. In contrast, CAR transactivation was significantly impaired in HepG2 cells stably expressing specific small interfering RNA directed against ASC-2. Consistent with these results, chromatin immunoprecipitation experiments revealed that ASC-2 is recruited to the known CAR target genes in a ligand-dependent manner. Secondly, CAR specifically interacted with the first LXXLL motif of ASC-2, and these interactions were stimulated by CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene and repressed by CAR inverse agonist androstanol, suggesting that this motif may mediate the interactions of ASC-2 and CAR in vivo. In support of this idea, DN1, a fragment of ASC-2 encompassing the first LXXLL motif, suppressed CAR transactivation, and coexpressed ASC-2 but not other LXXLL-type coactivators such as thyroid hormone receptor-associated protein 220 reversed this repression. Finally, CAR was recently found to play a pivotal role in effecting the severe acetaminophen-induced liver damage. Interestingly, transgenic mice expressing DN1 were resistant to the acetaminophen-induced hepatotoxicity and expression of a series of the known CAR target genes was specifically repressed in these transgenic mice. Taken together, these results strongly suggest that ASC-2 is a bona fide coactivator of the xenobiotic nuclear receptor CAR and mediate the specific xenobiotic response by CAR in vivo.
Molecular Endocrinology 08/2005; 19(7):1711-9. · 4.54 Impact Factor
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ABSTRACT: Insulin-induced gene-1 (Insig-1) and its homolog Insig-2 encode closely related proteins of the endoplasmic reticulum that block proteolytic activation of sterol regulatory element binding proteins, membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes. Herein, we identified a novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] response element in the promoter region of Insig-2 gene, which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. Interestingly, 1,25-(OH)2D3 is known to directly suppress the expression of peroxisome proliferator-activated receptor gamma2 protein and inhibits adipocyte differentiation of 3T3-L1 preadipocytes and murine bone marrow stromal cells. Consistent with an idea that the antiadipogenic action of 1,25-(OH)2D3 may also involve up-regulation of Insig-2, we found that 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR, and collectively our results suggest an intriguing, new linkage between 1,25-(OH)2D3 and lipogenesis.
Molecular Endocrinology 03/2005; 19(2):399-408. · 4.54 Impact Factor
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Seung-Whan Kim,
Keunhee Park,
Eunyee Kwak,
Eunho Choi, Seunghee Lee,
Jungyeob Ham,
Heonjoong Kang,
Jong Man Kim,
Seung Yong Hwang,
Young-Yun Kong,
Keesook Lee,
Jae Woon Lee
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ABSTRACT: Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXRalpha(-/-) mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRalpha in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.
Molecular and Cellular Biology 06/2003; 23(10):3583-92. · 5.53 Impact Factor
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ABSTRACT: Nuclear receptors adopt dramatically different conformations in the presence or absence of ligand, and such liganded (holo) and unliganded (apo) receptors are specifically recognized by transcriptional coactivators and corepressors, respectively. These two states likely exist in dynamic equilibrium, contrary to the conventional model of static off and on conformations. First, corepressor SMRT [for silencing mediator of thyroid hormone receptor (TR) and retinoic acid receptor (RAR)] inhibits the interaction of coactivator steroid receptor coactivator-1 with liganded TR/RAR. Second, SMRT enables receptors to adopt apo-form even in the presence of ligand, as demonstrated with limited proteolyses and decreased binding of radiolabeled retinoid to RAR. Finally, chromatin immunoprecipitation results indicate that SMRT and steroid receptor coactivator-1 dynamically compete for receptor bindings in vivo in the presence of ligand. These results suggest that corepressor binding can drive receptors to adopt the apo-state, even in the presence of ligand, and inhibit activated liganded (holo) nuclear receptors in vivo.
Molecular Endocrinology 04/2003; 17(3):366-72. · 4.54 Impact Factor
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ABSTRACT: Transcriptional regulation by nuclear hormone receptors (NRs) requires multiple coregulators that modulate chromatin structures by catalyzing a diverse array of posttranslational modifications of histones. Different combinations of these modifications yield dynamic functional outcomes, constituting an epigenetic histone code. This code is inscribed by histone‐modifying enzymes and decoded by effector proteins that recognize specific covalent marks. One important modification associated with active chromatin structures is methylation of histone H3‐lysine 4 (H3K4). Crucial roles for this modification in NR transactivation have been recently highlighted through our purification and subsequent characterization of a steady‐state complex associated with ASC‐2, a coactivator of NRs and other transcription factors. This complex, designated ASCOM for ASC‐2 complex, contains H3K4‐methyltransferase MLL3/HALR or its paralogue MLL4/ALR and represents the first Set1‐like H3K4‐methyltransferase complex to be reported in vertebrates. This review focuses on recent progress in our understanding of how ASCOM‐MLL3 and ASCOM‐MLL4 influence NR‐mediated gene transcription and of their physiological function.
Progress in Molecular Biology and Translational Science.
