Patrick Varga-Weisz

As of April 2018, Patrick has taken up a Lectureship in the School of Biological Sciences at the University of Essex. Visit his page there for full details of his current research.

Research Summary

Chromatin is a highly dynamic structure to accommodate its many tasks in regulating, organizing, safeguarding and packaging the genetic material. We are interested in understanding the mechanisms behind this sophisticated cellular machinery.

Key components that impart this dynamic state are special enzymes, so called chromatin remodelling factors, many of which target the nucleosome, the basic building block of chromatin.

The enzymology of chromatin remodelling is a largely new territory with opportunities for many exciting discoveries. One particular class of chromatin remodelling factors uses the energy gained by ATP hydrolysis to remodel nucleosomes: The nucleosome may be shifted, altered or blasted away, but some of these factors, such as Imitation Switch (ISWI), are also involved in nucleosome assembly.

The Varga-Weisz laboratory studies such ATP-dependent nucleosome remodelling factors, their role in the cell (in chromatin replication) and their mechanisms of action.

Latest Publications

Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.
Fellows R, Denizot J, Stellato C, Cuomo A, Jain P, Stoyanova E, Balázsi S, Hajnády Z, Liebert A, Kazakevych J, Blackburn H, Corrêa RO, Fachi JL, Sato FT, Ribeiro WR, Ferreira CM, Perée H, Spagnuolo M, Mattiuz R, Matolcsi C, Guedes J, Clark J, Veldhoen M, Bonaldi T, Vinolo MAR, Varga-Weisz P

The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.

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Nature communications, 9, 2041-1723, 105, 2018

PMID: 29317660

ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior.
Sun H, Damez-Werno DM, Scobie KN, Shao NY, Dias C, Rabkin J, Koo JW, Korb E, Bagot RC, Ahn FH, Cahill ME, Labonté B, Mouzon E, Heller EA, Cates H, Golden SA, Gleason K, Russo SJ, Andrews S, Neve R, Kennedy PJ, Maze I, Dietz DM, Allis CD, Turecki G, Varga-Weisz P, Tamminga C, Shen L, Nestler EJ

Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.

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Nature medicine, , 1546-170X, , 2015

PMID: 26390241

A novel phosphate-starvation response in fission yeast requires the endocytic function of Myosin I.
Petrini E, Baillet V, Cridge J, Hogan CJ, Guillaume C, Ke H, Brandetti E, Walker S, Koohy H, Spivakov M, Varga-Weisz P

Endocytosis is essential for uptake of many substances into the cell, but how it links to nutritional signalling is poorly understood. Here we show a novel role for endocytosis in regulating the response to low phosphate in Schizosaccharomyces pombe. Loss of function of Myo1, Sla2/End4 or Arp2, proteins involved in the early steps of endocytosis, led to increased proliferation in low phosphate media compared to controls. We show that once cells are deprived of phosphate they undergo a quiescence response that is dependent on the endocytic function of Myo1. Transcriptomic analysis revealed a wide perturbation of gene expression with induction of stress-regulated genes upon phosphate starvation in wildtype but not Δmyo1 cells. Thus, endocytosis plays a pivotal role in mediating the cellular response to nutrients, bridging the external environment and internal molecular functions of the cell.

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Journal of cell science, , 1477-9137, , 2015

PMID: 26345368