Role of UTX in Retinoic Acid Receptor-Mediated Gene Regulation in Leukemia

Rocha-Viegas, Luciana; Villa, Raffaella; Gutiérrez, Arantxa; Iriondo, Oihana; Shiekhattar, Ramin; Croce, Luciano Di

doi:10.1128/mcb.00839-14

Cited by 24 publications

(28 citation statements)

References 31 publications

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“…Utx was reported to trigger heart development through interaction with the cardiac TFs Tbx5, Nkx2.5, and GATA4 and binding to critical cardiac enhancers (82). Similarly, Utx was shown to interact with retinoic acid receptor a and to occupy several promoters of retinoic acid receptor a target genes leading to activation and proper differentiation of leukemic cells (83). p53, in turn, was reported to recruit Utx and JMJD3 to the regulatory regions of many developmental TFs leading to gene activation during human embryonic stem cell differentiation (84).…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

et al. 2015

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Adult skeletal muscles can regenerate after injury, due to the presence of satellite cells, a quiescent population of myogenic progenitor cells. Once activated, satellite cells repair the muscle damage by undergoing myogenic differentiation. The myogenic regulatory factors (MRFs) coordinate the process of progenitor differentiation in cooperation with other families of transcription factors (TFs). The Six1 and Six4 homeodomain TFs are expressed in developing and adult muscle and Six1 is critical for embryonic and adult myogenesis. However, the lack of a muscle developmental phenotype in Six4-null mice, which has been attributed to compensation by other Six family members, has discouraged further assessment of the role of Six4 during adult muscle regeneration. By employing genome-wide approaches to address the function of Six4 during adult skeletal myogenesis, we have identified a core set of muscle genes coordinately regulated in adult muscle precursors by Six4 and the MRF MyoD. Throughout the genome of differentiating adult myoblasts, the cooperation between Six4 and MyoD is associated with chromatin repressive mark removal by Utx, a demethylase of histone H3 trimethylated at lysine 27. Among the genes coordinately regulated by Six4 and MyoD are several genes critical for proper in vivo muscle regeneration, implicating a role of Six4 in this process. Using in vivo RNA interference of Six4, we expose an uncompensated function of this TF during muscle regeneration. Together, our results reveal a role for Six4 during adult muscle regeneration and suggest a widespread mechanism of cooperation between Six4 and MyoD.

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Section: Discussionmentioning

confidence: 99%

Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

et al. 2015

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“…These systematic analyses suggest three major groups of proteins interacting with UTX. 23 The second group of interacting proteins consists of DNA-binding transcription factors, especially nuclear receptors such as estrogen receptors, 5 retinoic acid receptors 24 and peroxisome proliferator-activated receptors. It comprises MLL2, MLL3, ASH2L, RBBP5, WDR5, NCOA6 (also known as AIB3), DPY30, PAXIP (also known as PTIP) and coordinates several biochemical processes associated with gene transcriptional activation, especially H3K4 methylation and H3K27me2/me3 demethylation.…”

Section: Protein Interactionsmentioning

confidence: 99%

“…As depicted in Figure 1b, UTX acts as a component of the MLL2/3 or "COMPASS" complex (described in the literature also as MLL3/MLL4 or ASCOM complex). 24 Interactions with nuclear receptors may be largely mediated by the NCOA6 protein. 12,[20][21][22] In addition, the complex can promote histone acetylation by the histone acetyltransferases p300 or CBP, chromatin remodeling via the SWI/SNF complex, as well as transcriptional elongation via interactions with transcription elongation factors and their associated histone-modifying proteins.…”

Section: Protein Interactionsmentioning

confidence: 99%

“…12,[20][21][22] In addition, the complex can promote histone acetylation by the histone acetyltransferases p300 or CBP, chromatin remodeling via the SWI/SNF complex, as well as transcriptional elongation via interactions with transcription elongation factors and their associated histone-modifying proteins. 23 The second group of interacting proteins consists of DNA-binding transcription factors, especially nuclear receptors such as estrogen receptors, 5 retinoic acid receptors 24 and peroxisome proliferator-activated receptors. 24 Interactions with nuclear receptors may be largely mediated by the NCOA6 protein.…”

Section: Protein Interactionsmentioning

confidence: 99%

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The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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The lysine‐specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T‐cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X‐chromosome, but both copies are expressed, may account for gender‐specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor‐suppressive function.

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“…Chromatin immunoprecipitation assays were performed as described previously (Bertucci et al 2013, Rocha-Viegas et al 2014) with chromatin obtained from adrenocortical Y1 cells, using ChIPAb+Phospho-CREB (Ser133) from Millipore (EMD Millipore) and IgG (kch-504-250) from Diagenode (Denville, NJ, USA) as a negative control. Research 57 2 : …”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

Astort

Repetto

Rocha-Viegas

et al. 2016

Journal of Molecular Endocrinology

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In addition to the well-known function of ACTH as the main regulator of adrenal steroidogenesis, we have previously demonstrated its effect on the transcriptional stimulation of HO-1 expression, a component of the cellular antioxidant defense system. In agreement, we hereby demonstrate that, in adrenocortical Y1 cells, HO-1 induction correlates with a significant prevention of the generation of reactive oxygen species induced by H 2 O 2 /Fe 2+ . ACTH/cAMP-dependent activation of redox-imbalanced related factors such as NRF2 or NFκB and the participation of MAPKs in this mechanism was, however, discarded based on results with specific inhibitors and reporter plasmids. We suggest the involvement of CREB in HO-1 induction by ACTH/cAMP, as transfection of cells with a dominant-negative isoform of CREB (DN-CREB-M1) decreased, while overexpression of CREB increased HO-1 protein levels. Sequence screening of the murine HO-1 promoter revealed CRE-like sites located at −146 and −37 of the transcription start site and ChIP studies indicated that this region recruits phosphorylated CREB (pCREB) upon cAMP stimulation in Y1 cells. In agreement, H89 (PKA inhibitor) or cotransfection with DN-CREB-M1 prevented the 8Br-cAMP-dependent increase in luciferase activity in cells transfected with pHO-1[−295/+74].LUC. ACTH and cAMP treatment induced the activation of the PI3K/Akt signaling pathway in a PKA-independent mechanism. Inhibition of this pathway prevented the cAMP-dependent increase in HO-1 protein levels and luciferase activity in cells transfected with pHO-1[−295/+74].LUC. Finally, here we show a crosstalk between the cAMP/PKA and PI3K pathways that affects the binding of p-CREB to its cognate element in the murine promoter of the Hmox1 gene. CREB mediates adrenal HO-1 induction by cAMPf astort, e m repetto and others (Gallo-Payet 2016). In turn, stimulation of PKA activity is involved in the phosphorylation and activation of several transcription factors engaged in the transcriptional stimulation of steroidogenic-related genes. Among them, the cAMP response element binding protein (CREB), the GATA-4 binding protein, the steroidogenic factor 1 (SF1) and the CAAT enhancer binding protein (C/EBP) could be included (Manna et al. 2003a,b, Stocco et al. 2005.Glucocorticoid synthesis in the adrenal cortex is a multistep process where mitochondrial and microsomal cytochrome P450 enzymes, mixed function oxidases, catalyze the hydroxylation of steroids and the reduction of O 2 to water. Even under physiological conditions, ACTHstimulated steroidogenesis generates oxidative stress, as incomplete reduction in O 2 leads to the production of reactive oxygen species (ROS), lipoperoxides and other oxygenated species (Hanukoglu 2006, Prasad et al. 2014. To cope with the potentially damaging effects associated with oxidative stress, adrenal cells activate several antioxidant mechanisms (Chinn et al. 2002, Hanukoglu 2006, Battista et al. 2009). Among them, we have previously shown that the ACTH-dependent induction of heme oxygenase...

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Role of UTX in Retinoic Acid Receptor-Mediated Gene Regulation in Leukemia

Cited by 24 publications

References 31 publications

Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Role of CREB on heme oxygenase-1 induction in adrenal cells: involvement of the PI3K pathway

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