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The Creyghton group uses comparative epigenomics to study changes in gene regulation during linked to human evolution, development and disease.
Deciphering how cells can exist in the diverse cellular states that make up a functional organism while carrying the same genomic information is a major challenge in biology. Transcription factors are responsible for the deposition of epigenomic modifications upon the genome that serve as instructions as to how the genome is being read in each different cell type, thus allowing the cell to adopt a specialized state. Furthermore, these instructions are highly dynamic and can change under the influence of extracellular cues presenting the cells with the ability to respond to changes in their environment.
Distal enhancers have emerged as key regulatory non-coding structures in the mammalian genome that support gene expression over long distances. We have identified a host of new enhancer regions in several different cell types and have shown that these enhancer networks are active in a cell state dependent manner and control cellular identity. Furthermore, we provided evidence that enhancers can be divided between inactive, active and poised configurations based on specific histone modifications, providing insight into the limitations of a cells ability to respond to environmental cues. Therefore, cellular identity can be largely described by the genome wide activity of its enhancer networks.
The location of gene regulatory elements in the human genome has long been unknown as these elements are poorly conserved and located in large stretches of non-coding gene deserts. Our laboratory uses specific epigenomic signatures to locate these regulatory elements across the genome. Being largely species specific as well as affected by in vitro culture it is critical to study the epigenomic patterns at regulatory elements in their relevant context. Understanding the regulatory networks that govern the human brain therefore requires analysis of human brain tissue. We have recently published a large compendium of ChIP sequencing datasets derived from post mortem human brain tissue which can be found here. This allowed the large-scale identification of enhancer networks specific to the human brain. Our lab is using these data to further understand the human brain, its place in evolution and its diseases.
The brain is a highly heterogeneous tissue with different neural and glial cell types. Therefore, epigenomic information amplifies the commonalities of its resident cell types while diluting the specific information. We use co-regulation of enhancers to identify small networks of enhancers in the brain that appear to contain cell type as well as context specific activity (1). Additionally we are developing several techniques to further increase the resolution of ChIP sequencing data in complex tissue towards single cell type resolution.
Several diseases are known to be caused by mutations in non-coding enhancer elements such as Hirschsprung’s disease, thalassemias, preaxial polydactyly and lymphoma. These discoveries not only have established enhancers as potential disease-causing structures in the genome when mutated, but also explain the tissue specific manifestation of disease phenotypes. Many diseases of unknown origin might be supported by dysfunctional enhancers and alterations at groups of enhancers are believed to underlie variations in disease susceptibility. This is especially true for complex diseases such as neurodegenerative disease, which in most cases lack a clearly defined genetic causative component. Our lab is currently identifying disease associated non-coding elements in the brain that are involved in Parkinson’s disease.
The human brain is widely considered to represent the crown on the late evolutionary emergence of the human lineage separating humans from other animal species. However, the extent to which the human brain is special and the identity of the genomic alterations involved are still a matter of intense debate. Especially changes at non-coding DNA have been difficult to link to functional evolutionary alterations. We are currently annotating regulatory elements in the genome of various primate species to uncover which genomic alterations are functionally relevant and have potentially contributed to the late evolution of the human brain. In doing so we hope to gain valuable insight into the rules underlying the emergence of the human brain as well as the relevance of primate models for human neurodegenerative disease (2).
Epigenetic deregulation of gene regulatory elements that control oncogenes and tumor suppressors has been shown to underlie cancer development and progression in a number of systems. Furthermore, genes involved in the regulation of the epigenome are often found affected by mutations in cancer. This raises the possibility that in some cases, the cell state changes associated with cancer could have an epigenetic rather than a genetic basis. We are studying several distinct cancer states using patient material to uncover the regulatory mechanisms that allow a cell to become cancerous or evolve to a state that allows escape from treatment. The results of these studies could be used to device new therapeutic strategies.
Vermunt, M.W., Tan S.C., Castelijns B., Geeven, G., Reinink, P., de Bruijn, E., Kondova I., Persengiev S., Netherlands Brain Bank; Bontrop R., Cuppen, E., de Laat, W. and Creyghton M.P.
Vermunt, M.W., Reinink, P., Korving J., de Bruijn, E., Creyghton, P.M., Basak, O., Geeven, G., Toonen, P.W., Lansu, N., Meunier, C., Heesch, S., Netherlands Brain Bank; Clevers, H., de Laat, W., Cuppen, E. and Creyghton M.P.
Creyghton, M.P., Cheng, A., Welstead, G.G., Kooistra, T., Carey, B.W., Steine, E.J., Hanna, J., Lodato, M.A., Frampton ,G.M., Sharp, P.A., Boyer, L.A., Young, R.A., Jaenisch, R.
Geeven G., Zhu Y., Kim B.J., Bartholdy B.A., Yang S.M., Macfarlan T.S., Gifford W.D., Pfaff S.L., Verstegen M.J., Pinto H., Vermunt M.W., Creyghton M.P., Wijchers P.J., Stamatoyannopoulos J.A., Skoultchi A.I., de Laat W.
Peeters J.G., Vervoort S.J., Tan S.C., Mijnheer G., de Roock S., Vastert S.J., Nieuwenhuis E.E., van Wijk F., Prakken B.J., Creyghton M.P., Coffer P.J., Mokry M., van Loosdregt J.
Kanski, R., Sneeboer, M., van Bodegraven, E., Sluijs, J.A., Kropff, W.W., Vermunt, M.W., Creyghton, M.P., De Filippis, L., Vescovi, A., Aronica, E., van Tijn, P., van Strien, M and Hol, E.
Welstead G.G., Creyghton, M.P., Bilodeau S., Cheng A.W., Markoulaki S., Young R.A., Jaenisch R.
Carey B.W., Markoulaki S., Hanna, J., Faddah D.A., Buganim Y, Kim J, Ganz K, Steine E.J., Cassady J.P., Creyghton, M.P., Welstead G.G., Gao Q, Jaenisch R.
Hanna, J., Saha, K., Pando, B., van Zon, B., Lengner, C.J., Creyghton, M.P., van Oudenaarden, A., Jaenisch, R.
Creyghton, M.P., Markoulaki, S., Levine, S., Hanna, J., Lodato, M.A., Sha, K., Young, R.A., Jaenisch, R., Boyer, L.A.
Hanna, J., Markoulaki, S., Schorderet, P., Carey, B.W., Beard, C., Wernig, M., Creyghton, M.P., Steine, E.J., Cassady, J.P., Foreman, R., Lengner, C.J., Dausman, J.A. & Jaenisch, R.
Eichhorn P.J., Creyghton, M.P., Bernards R.
Eichhorn P.J., Creyghton, M.P., Wilhelmsen K., van Dam H., Bernards R.
Creyghton, M.P., Roël G, Eichhorn P.J., Vredeveld L.C., Destrée O., Bernards R.
Creyghton, M.P., Roël G, Eichhorn P.J., Hijmans E.M., Maurer I., Destrée O., Bernards R.
Menno Creyghton is group leader at the Hubrecht Institute. His group studies in the complex epigenomic landscape of the brain using large scale ChIP-sequencing experiments on human brain tissue. These experiments are combined with functional assays in stem cells and model organisms in order to understand the cell state changes that underlie development and evolution of the human brain, and also its susceptibility to disease, such as neurodegenerative diseases and cancer.
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