Lars Grøntved obtained a PhD in Molecular Biology from the University of Southern Denmark in 2008. He did postdoctoral research with Gordon Hager at the National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, USA. Here he used functional genomics technology (e.g. DNase-seq and ChIP-seq) to study basic mechanisms regulating transcription factor (focus of Nuclear hormone receptors) interaction with chromatin. He specifically developed technology to probe for chromatin accessibility in tissue and collaborated with several NIH investigators to implement the technology. For his research at NIH he received a NCI Directors Intramural Innovation Award and a NIH Directors Award. In 2014 he joined the Department of Biochemistry and Molecular Biology at SDU as an Assistant Professor.
Head of research: Assistant Professor Lars Grøntved
PhD student Stine Marie Præstholm
General description of research area
Many differentiated tissues possess striking transcriptional plasticity in response to metabolic changes. E.g. circadian regulation of the hepatic transcriptome, activation of B-cells during an immune response and browning of white adipocytes by cold exposure. This ability to adapt to the environment is essential for the organism; however adaptation is often linked to pathophysiology of disease such as obesity and diabetes. We aim to understand the underlying mechanisms for the environmental impact on gene transcription and study how the individual genome sequence directly affect the chromatin structure and the ability to react to the environment. We use the mouse liver as a model system and advanced functional genomics technology to understand the organization of chromatin structure genome-wide (see figure). The research is funded by grants from SDU2020, the Danish diabetes academy, the Novo Nordisk Foundation and the Danish research council.
Current research projects
Identification of Novel Mechanisms Regulating Hepatic Transcriptional Response to High Fat Diet
Diet induced obesity is associated with hepatic transcriptional reprogramming regulated by multiple transcription factors. In the past these processes have mostly been described by relative simple gene-by-gene approaches. This project use genome-wide technologies such as DNase-seq, ChIP-seq and RNA-seq to characterize hepatic changes to chromatin structure and transcriptional reprogramming in response to high fat diet. The aim is identify differentially regulated hepatic transcriptional networks associated with diet-induced obesity.
Transcriptional Signaling Networks Regulating Acute Hepatic Response to Feeding
Hepatic transcriptional oscillation such as circadian rhythm is tightly coupled to diet composition and temporal feeding pattern. Whereas the diurnal genome-wide changes in hepatic chromatin structure have been studied extensively little is known about dynamic regulation of chromatin organization in response to feeding per se. This project seeks to characterize structural changes to chromatin structure in response to acute feeding and relate chromatin remodeling with transcriptional reprogramming. Moreover the project aims to identify the underlying mechanisms controlling acute feeding regulated chromatin structure remodeling.
Principles behind ChIP-seq and DNase-seq genomics based approaches. A) Example of a functional genomics approach to identify deregulated transcriptional pathways in tissue from different mouse models. B) Illustration of chromatin and techniques to enrich for specific functional regions genome wide. Genomic DNA is compacted by chromatin in the nucleus. The basal unit of chromatin is genomic DNA wrapped around nucleosomes, octamers of two H2A, H2B, H3 and H4 (collectively shown here as green spheres) and compacted further by H1 (purple). In a given cell most of chromatin is inaccessible to regulatory proteins such as transcription factors (TFs). However at specific regulatory regions sequence specific transcription factors can interact with genomic DNA. These regulatory regions are characteristic by enrichment of neighboring posttranslational modified histones (e.g H3K27Ac). Moreover these regulatory regions are characterized by accessibility to DNase I. Importantly DNase I can not access chromatin inaccessible to transcription factors. Thus regulatory regions can be very efficiently identified using DNase I treatment of chromatin in the nucleus. Liberated small DNA fragments can be purified using sucrose gradients and sequenced to obtain genome wide information on accessibility. In parallel chromatin can be crosslinked using formaldehyde (crosslink DNA and protein). Immunoprecipitation of crosslinked chromatin with specific antibodies against histone modifications and transcription factors will enrich for regions where modified histones and TFs interact with the genome. Enriched regions can be sequenced to obtain a genome wide map of interactions. C) RNAPII occupancy, histone modifications and DNase accessibility at the albumin gene in adult mouse liver. Grey marks regulatory accessible regions. A genome wide collection of regulatory elements functions as bioinformatical input to generate transcription regulatory networks.
Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.
Grøntved L, Waterfall JJ, Kim DW, Baek S, Sung MH, Zhao L, Park JW, Nielsen R, Walker RL, Zhu YJ, Meltzer PS, Hager GL, Cheng SY. Nature Communications. 2015 Apr 28;6:7048.
C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements.
Grøntved L, John S, Baek S, Liu Y, Buckley JR, Vinson C, Aguilera G, Hager GL. EMBO J. 2013 May 29;32(11):1568-83.
Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.
Kieffer-Kwon KR, Tang Z, Mathe E, Qian J, Sung MH, Li G, Resch W, Baek S, Pruett N, Grøntved L, Vian L, Nelson S, Zare H, Hakim O, Reyon D, Yamane A, Nakahashi H, Kovalchuk AL, Zou J, Joung JK, Sartorelli V, Wei CL, Ruan X, Hager GL, Ruan Y, Casellas R. Cell. 2013 Dec 19;155(7):1507-20.
A full list of publications by assistant professor Lars Grøntved can be found here.