Interplay between the Chd4/NuRD Complex and the Transcription Factor Znf219 Controls Cardiac Cell Identity

The sarcomere regulates striated muscle contraction. This structure is composed of several myofibril proteins, isoforms of which are encoded by genes specific to either the heart or skeletal muscle. The chromatin remodeler complex Chd4/NuRD regulates the transcriptional expression of these specific sarcomeric programs by repressing genes of the skeletal muscle sarcomere in the heart. Aberrant expression of skeletal muscle genes induced by the loss of Chd4 in the heart leads to sudden death due to defects in cardiomyocyte contraction that progress to arrhythmia and fibrosis. Identifying the transcription factors (TFs) that recruit Chd4/NuRD to repress skeletal muscle genes in the myocardium will provide important information for understanding numerous cardiac pathologies and, ultimately, pinpointing new therapeutic targets for arrhythmias and cardiomyopathies. Here, we sought to find Chd4 interactors and their function in cardiac homeostasis. We therefore describe a physical interaction between Chd4 and the TF Znf219 in cardiac tissue. Znf219 represses the skeletal-muscle sarcomeric program in cardiomyocytes in vitro and in vivo, similarly to Chd4. Aberrant expression of skeletal-muscle sarcomere proteins in mouse hearts with knocked down Znf219 translates into arrhythmias, accompanied by an increase in PR interval. These data strongly suggest that the physical and genetic interaction of Znf219 and Chd4 in the mammalian heart regulates cardiomyocyte identity and myocardial contraction.J.V. was supported by the Spanish Ministry of Science and Innovation (PGC2018-097019-B-I00 and PID2021-122348NB-I00), UE Funds and Micinn-Inst Carlos III (PMP21_00057) and “la Caixa” Banking Foundation (project codes HR17-00247 and HR22-00253). J.M.R. was supported by the La Caixa Banking Foundation (project code HR18-00068), the Spanish Ministry of Science and Innovation grant RTI2018-099246-B-I00 (MICIU/AEI/FEDER, UE); the Comunidad de Madrid and European Social Fund (ESF) grant AORTASANA-CM (B2017/BMD-3676); and the Instituto de Salud Carlos III (ISCIII) (CIBER-CVCB16/11/00264). PG-A was supported by Spanish Ministry of Science and Innovation (grants SAF2016-77816-P and PID2020-114773GB-I00). The CNIC is supported by Instituto de Salud Carlos III (ISCIII), the Spanish Ministry of Science and Innovation and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by Spanish Ministry of Science and Innovation AEI/10.13039/501100011033). FAS is supported by a Science and Innovation Fellowship (BES-2017-080629).S

Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model

Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia

Functional Characterization of the Cardiac Development of A rrhythmias and Dysfunction: Role of Chd4, Znf219 and ThPOK interaction

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 12-01-2023Esta Tesis tiene embargado el acceso al texto completo hasta el 12-07-2024The physiological function of adult cardiomyocytes depends largely on the fine regulation of gene expression during both development and adulthood. For adequate contraction, myocardium-specific actomyosin complexes must be assembled, forming cross-bridges, which subsequently generate sufficient energy to propel blood to the rest of the organism. This too allows tissue relaxation during the refractory period, thus avoiding myocardial tetanization. A regulator of cardiomyocyte gene expression is the chromatin remodeler Chd4/NuRD, which maintains cardiac muscle identity by repressing the expression of skeletal muscle sarcomeric genes. In the absence of Chd4/ N uRD, cardiomyocytes are thus “hybrid myocytes”, containing both cardiac and skelet al myofibril components. These aberrantly expressed proteins intercalate in the cardiac sarcomere causing impairment of cardiac function, which translates to arrhythmias, fibrosis and ventricular dysfunction leading to sudden death. The identification of transcription factors (TFs) that recruit Chd4/NuRD to repress skeletal muscle genes in the myocardium is therefore seminal for understanding cardiac physiology. Alterations in these molecular interactions may unveil numerous cardiac pathologies and ultimately point to new therapeutic targets for arrhythmias and cardiomyopathies. In this thesis, we attempt to find and describe some of the TFs t hat genetically and/or physically interact with Chd4/NuRD, and their role in cardiac homeostasis. Thus, we first describe the synergistic transcriptional repression of the pro-apoptotic protein Sprr1a by Chd4 and the TF ThPOK, whose aberrant expression produces ventricular dysfunction and severe arrhythmias, such as atrial fibrillation and n on-sustained polymorphic ventricular fibrillation, ultimately resulting in heart failure a nd sudden death. We secondly describe a physical interaction between Chd4 and the TF Znf219 i n cardiac tissue. Znf219 represses in vitro and in vivo t he skeletal muscle sarcomeric program in cardiomyocytes, similarly to Chd4. Aberrant expression of skeletal muscle sarcomere proteins in Znf219-knockdown mouse hearts results in arrhythmias, accom - panied by an increased PR interval. These data strongly suggest that the physical and genetic interaction of Znf219 and Chd4 in the mammalian heart regulates cardiomyo - cyte identity and myocardial contractionT his thesis was performed in the laboratory of Pablo Gómez del Arco and J uan Miguel Redondo Moya, mostly in theInstituto de Salud Carlos III (ISCIII) a nd Centro Nacional de Investigaciones Cardiovasculares (CNIC). This study was f unded by the Science Ministry and Innovation of Spain (MICINN) under the proj - e ct codes SAF2016-77816-P and PID2020-114773GB-I00. Fadoua El Abdellaoui S oussi was awarded a FPI fellowship (BES-2017-080629)

En busca del origen de las arritmias cardiacas

Artículo de divulgación publicado en The Conversation España el día 12/12/2022.Las investigaciones de los autores han localizado dos proteínas que desempeñan un papel fundamental para que nuestro corazón lata -o deje de hacerlo- a un ritmo acompasado.N

Role of Chromodomain-Helicase-DNA-Binding protein 4 (CHD4) in Breast Cancer

Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4—the core component of the nucleosome remodeling and deacetylase (NuRD) complex—may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either ‘deleterious’, ‘probably/possibly damaging’ or as ‘high/medium pathogenic’; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.Ministry of Science and Innovation of Spain MICINN (grant no. SAF2016-77816-P)Fundación de la Universidad Europea (project numbers XSAN001907 and XFGU001903)MICINN (no. BES-2017-080629)6.244 JCR (2020) Q2, 62/242 Oncology1.834 SJR (2020) Q1, 61/354 OncologyNo data IDR 2020UE