Indrabahadur Singh

German Cancer Research Center

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Guillermo Barreto

Université de Lorraine

Werner Seeger

Universities of Giessen and Marburg Lung Center

Thomas Braun

Max Planck Institute for Heart and Lung Research

Mathias Heikenwälder

Heidelberg University

Julio Cordero

German Centre for Cardiovascular Research

Karla Rubio

Max Planck Institute for Heart and Lung Research

Aditi Mehta

Post Graduate Institute of Medical Education and Research

Savério Bellusci

Universities of Giessen and Marburg Lung Center

Rajkumar Savai

University of Giessen

Reinhard Dammann

University of Giessen

Cooperative Institutions

Heidelberg University

111

German Cancer Research Center

German Center for Lung Research

Inserm

University Hospital Heidelberg

Helmholtz Zentrum München

European Foundation for the Study of Chronic Liver Failure

DKFZ-ZMBH Alliance

Max Planck Institute for Heart and Lung Research

Technical University of Munich

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HMGA2 mediated epigenetic regulation of Gata6 controls epithelial WNT signaling during lung development

Indrabahadur Singh Aditi Mehta Nihan Öztürk Julio Cordero Adriana Contreras

Organ regeneration requires a proper balance between self-renewal and differentiation of tissue specific progenitor cells. Progenitor expansion and differentiation recapitulate many of the mechanisms regulating embryonic development. Here, we uncovered the role of the high mobility group AT-hook protein 2 (HMGA2) as a key regulator of epithelial differentiation during embryonic lung development. Hmga2 loss-of-function increased WNT signaling resulting not only in defective epithelial differentiation but also expansion of progenitors in the developing lung. We found that HMGA2 direct regulation of Gata6 is crucial in fine-tuning WNT signaling in airway epithelium. Furthermore, we combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results also link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Together, our data demonstrate that HMGA2-mediated changes in chromatin structure regulate WNT signaling and control the balance between progenitor expansion and differentiation required for proper lung development. Ref: Singh I, et al., (2015) Cell Research; Jul;25(7):837-50 Singh I, et al., (2014) BMC Biol; Mar 24;12:21 Ozturk N, Singh I, et al., (2014) Front Cell Dev Biol.; Mar 6;2:5

HMGA2

GATA6

10.1183/1393003.congress-2017.oa3228

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Citations (1)

Dysregulated epigenetic factors in non-alcoholic fatty liver disease and triggered liver cancer

Zeitschrift für Gastroenterologie (2019)

Indrabahadur Singh Valentina Leone X Li Dominik Pfister Mira Stadler

Already, almost a quarter of the world's population suffers from non-alcoholic fatty liver (NAFLD) and this problem is steadily increasing. Non-alcoholic steatohepatitis (NASH), the chronic progressive manifestation of NAFLD, is the second most important cause of hepatocellular carcinoma (HCC). NAFLD thus represents a major socio-economic burden on the health care system and is of increasing importance. There are currently no drugs nor therapies that can treat NASH or stop the progression of the disease to HCC. At the same time, treatment options for HCC are limited and many patients show resistance to sorafenib, the only drug currently approved for first-line therapy. Although there have been major advances uncovering the genetic basis for NAFLD and HCC, the epigenetic mechanisms driving HCC remains largely elusive. Nevertheless, recent studies suggest epigenetic manipulation could be a promising approach to prevent the progression of NAFLD and HCC. Pan-Histone deacetylase (Pan-HDAC) inhibitors (e.g. Verinostat, PXD-101, Resminostat) are under clinical trials for HCC therapy. Pan-HDAC inhibitors have side effects and most importantly, others and we have observed that specific genetic knockouts of HDAC (e.g. HDAC3 and HDAC2) induce liver cancer under normal condition. We require more specific and alternate approach to develop therapy against this deadly disease. Epigenetic mechanisms underlying NAFLD progression remain elusive. Here, we are systematically investigating epigenetic factors that regulate NASH and transition to HCC in recently established our diet-induced NASH/HCC mouse models that recapitulate pathophysiological aspects of human NASH/HCC. Employing mass-spectrometry and next generation sequencing, we have identified putative targets that will be characterized and exploited for developing potential therapeutics for this deadly disease.

Steatohepatitis

Epigenetic Therapy

Liver disease

Liver Cancer

Chronic liver disease

10.1055/s-0038-1677184

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HMGA proteins as modulators of chromatin structure during transcriptional activation

Frontiers in Cell and Developmental Biology (2014)

Nihan Öztürk Indrabahadur Singh Aditi Mehta Thomas Braun Guillermo Barreto

High mobility group (HMG) proteins are the most abundant non-histone chromatin associated proteins. HMG proteins bind to DNA and nucleosome and alter the structure of chromatin locally and globally. Accessibility to DNA within chromatin is a central factor that affects DNA-dependent nuclear processes such as transcription, replication, recombination and repair. HMG proteins associate with different multi-protein complexes to regulate these processes by mediating accessibility to DNA. HMG proteins can be subdivided into three families: HMGA, HMGB and HMGN. In this review, we will focus on recent advances in understanding the function of HMGA family members, specifically their role in gene transcription regulation during development and cancer.

High-mobility group

Histone-modifying enzymes

Pioneer factor

10.3389/fcell.2014.00005

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Citations (126)

Non‐invasive lung cancer diagnosis by detection ofGATA6andNKX2‐1isoforms in exhaled breath condensate

EMBO Molecular Medicine (2016)

Aditi Mehta Julio Cordero Stephanie Dobersch Addi J. Romero-Olmedo Rajkumar Savai

Abstract Lung cancer ( LC ) is the leading cause of cancer‐related deaths worldwide. Early LC diagnosis is crucial to reduce the high case fatality rate of this disease. In this case–control study, we developed an accurate LC diagnosis test using retrospectively collected formalin‐fixed paraffin‐embedded ( FFPE ) human lung tissues and prospectively collected exhaled breath condensates ( EBC s). Following international guidelines for diagnostic methods with clinical application, reproducible standard operating procedures ( SOP ) were established for every step comprising our LC diagnosis method. We analyzed the expression of distinct mRNA s expressed from GATA 6 and NKX 2‐1 , key regulators of lung development. The Em/Ad expression ratios of GATA 6 and NKX 2‐1 detected in EBC s were combined using linear kernel support vector machines ( SVM ) into the LC score, which can be used for LC detection. LC score‐based diagnosis achieved a high performance in an independent validation cohort. We propose our method as a non‐invasive, accurate, and low‐price option to complement the success of computed tomography imaging ( CT ) and chest X‐ray ( CXR ) for LC diagnosis.

Exhaled breath condensate

10.15252/emmm.201606382

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Preliminary results from the EMoLung clinical study showing early lung cancer detection by the LC score

Discover Oncology (2023)

Karla Rubio Jason M. Müller Aditi Mehta Iris Watermann Till Olchers

Lung cancer (LC) causes more deaths worldwide than any other cancer type. Despite advances in therapeutic strategies, the fatality rate of LC cases remains high (95%) since the majority of patients are diagnosed at late stages when patient prognosis is poor. Analysis of the International Association for the Study of Lung Cancer (IASLC) database indicates that early diagnosis is significantly associated with favorable outcome. However, since symptoms of LC at early stages are unspecific and resemble those of benign pathologies, current diagnostic approaches are mostly initiated at advanced LC stages.We developed a LC diagnosis test based on the analysis of distinct RNA isoforms expressed from the GATA6 and NKX2-1 gene loci, which are detected in exhaled breath condensates (EBCs). Levels of these transcript isoforms in EBCs were combined to calculate a diagnostic score (the LC score). In the present study, we aimed to confirm the applicability of the LC score for the diagnosis of early stage LC under clinical settings. Thus, we evaluated EBCs from patients with early stage, resectable non-small cell lung cancer (NSCLC), who were prospectively enrolled in the EMoLung study at three sites in Germany.LC score-based classification of EBCs confirmed its performance under clinical conditions, achieving a sensitivity of 95.7%, 91.3% and 84.6% for LC detection at stages I, II and III, respectively.The LC score is an accurate and non-invasive option for early LC diagnosis and a valuable complement to LC screening procedures based on computed tomography.

10.1007/s12672-023-00799-9

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Citations (3)

Hmga2is required for canonical WNT signaling during lung development

BMC Biology (2014)

Indrabahadur Singh Aditi Mehta Adriana Contreras Thomas Boettger Gianni Carraro

The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2 −/− ). We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2 −/− mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/progenitor cells during lung regeneration in both homeostatic turnover and repair after injury.

HMGA2

LRP5

AXIN2

LRP6

10.1186/1741-7007-12-21

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Citations (61)

Combining ALT/AST Values with Surgical APGAR Score Improves Prediction of Major Complications after Hepatectomy

Journal of Surgery and Research (2021)

Ivaylo Mitsiev Karla Rubio Vikas P. Ranvir Diana Yu Arun P. Palanisamy

Hepatectomy is a complex procedure with high morbidity and mortality. Early prediction/prevention of major complications is highly valuable for patient care. Surgical APGAR score (SAS) has been validated to predict post-surgical complications (PCs). We aimed to define a simple complications classification following hepatectomy based on a therapy-oriented severity Clavien-Dindo classification (CDC). 119 patients undergoing liver resection were included. PCs were determined at follow-up based on CDC. Clinicopathological factors were used to calculate SAS. A receiver-operator characteristic (ROC) curve analysis estimated the predictive value of SAS for PCs. Circulating markers levels of liver injury were analyzed as critical elements on PCs. SAS (P=0.008), estimated blood-loss (P=0.018) and operation time (P=0.0008) were associated with PCs. SAS was reduced in patients with (+) compared to those without (-) complications (6.64±1.84 vs 5.70±1.79, P=0.0079). The area-under-the-curve was 0.646 by ROC, indicating an acceptable discrimination with 65% possibility to distinguish (-) and (+) groups (P=0.004). Best cutoff value for SAS was ≤6/≥7, at which sensitivity and specificity were maximal. ALT/ASL levels were significantly different within the group with 9-10 SAS points (P=0.01 and 0.02). In conclusion, SAS provides accurate risk stratification for major PCs after hepatectomy, and might help improving the overall patient outcome.

Cut-off

Risk Stratification

10.26502/jsr.10020179

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Citations (4)

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs

International Journal of Molecular Sciences (2023)

Karla Rubio Alejandro Molina-Herrera Andrea Pérez-González Hury Viridiana Hernández‐Galdámez Carolina Piña‐Vázquez

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

Histone acetyltransferase

10.3390/ijms241512302

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Citations (16)

Editorial: Metabolism and Epigenetics

Frontiers in Genetics (2022)

Carlos Sebastián Joaquim S. L. Vong Manasi K. Mayekar Krishna Seshu Tummala Indrabahadur Singh

EDITORIAL article Front. Genet., 10 March 2022Sec.Epigenomics and Epigenetics https://doi.org/10.3389/fgene.2022.877538

10.3389/fgene.2022.877538

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Citations (4)

Direct inhibition of oncogenic KRAS by Bacillus pumilus ribonuclease (binase)

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2016)

О. N. Ilinskaya Indrabahadur Singh Elena Dudkina Vera Ulyanova Airat R. Kayumov

10.1016/j.bbamcr.2016.04.005

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Citations (42)