Life Sciences Research for Lifelong Health

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

Transcriptome analysis identifies a robust gene expression program in the mouse intestinal epithelium on aging.
Kazakevych J, Stoyanova E, Liebert A, Varga-Weisz P

The intestinal epithelium undergoes constant regeneration driven by intestinal stem cells. How old age affects the transcriptome in this highly dynamic tissue is an important, but poorly explored question. Using transcriptomics on sorted intestinal stem cells and adult enterocytes, we identified candidate genes, which change expression on aging. Further validation of these on intestinal epithelium of multiple middle-aged versus old-aged mice highlighted the consistent up-regulation of the expression of the gene encoding chemokine receptor Ccr2, a mediator of inflammation and several disease processes. We observed also increased expression of Strc, coding for stereocilin, and dramatically decreased expression of Rps4l, coding for a ribosome subunit. Ccr2 and Rps4l are located close to the telomeric regions of chromosome 9 and 6, respectively. As only few genes were differentially expressed and we did not observe significant protein level changes of identified ageing markers, our analysis highlights the overall robustness of murine intestinal epithelium gene expression to old age.

+ View Abstract

Scientific reports, 9, 2045-2322, 10410, 2019

PMID: 31320724

Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism.
Fachi JL, Felipe JS, Pral LP, da Silva BK, Corrêa RO, de Andrade MCP, da Fonseca DM, Basso PJ, Câmara NOS, de Sales E Souza ÉL, Dos Santos Martins F, Guima SES, Thomas AM, Setubal JC, Magalhães YT, Forti FL, Candreva T, Rodrigues HG, de Jesus MB, Consonni SR, Farias ADS, Varga-Weisz P, Vinolo MAR

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.

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Cell reports, 27, 2211-1247, 750-761.e7, 2019

PMID: 30995474

A SUV39H1-low chromatin state characterises and promotes migratory properties of cervical cancer cells.
Rodrigues C, Pattabiraman C, Vijaykumar A, Arora R, Narayana SM, Kumar RV, Notani D, Varga-Weisz P, Krishna S

Metastatic progression is a major cause of mortality in cervical cancers, but factors regulating migratory and pre-metastatic cell populations remain poorly understood. Here, we sought to assess whether a SUV39H1-low chromatin state promotes migratory cell populations in cervical cancers, using meta-analysis of data from The Cancer Genome Atlas (TCGA), immunohistochemistry, genomics and functional assays. Cervical cancer cells sorted based on migratory ability in vitro have low levels of SUV39H1 protein, and SUV39H1 knockdown in vitro enhanced cervical cancer cell migration. Further, TCGA SUV39H1-low tumours correlated with poor clinical outcomes and showed gene expression signatures of cell migration. SUV39H1 expression was examined within biopsies, and SUV39H1 cells within tumours also demonstrated migratory features. Next, to understand genome scale transcriptional and chromatin changes in migratory populations, cell populations sorted based on migration in vitro were examined using RNA-Seq, along with ChIP-Seq for H3K9me3, the histone mark associated with SUV39H1. Migrated populations showed SUV39H1-linked migratory gene expression signatures, along with broad depletion of H3K9me3 across gene promoters. We show for the first time that a SUV39H1-low chromatin state associates with, and promotes, migratory populations in cervical cancers. Our results posit SUV39H1-low cells as key populations for prognosis estimation and as targets for novel therapies.

+ View Abstract

Experimental cell research, , 1090-2422, , 2019

PMID: 30772380

 

Group Members

Latest Publications

Transcriptome analysis identifies a robust gene expression program in the mouse intestinal epithelium on aging.

Kazakevych J, Stoyanova E, Liebert A

Scientific reports
9 2045-2322:10410 (2019)

PMID: 31320724

Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism.

Fachi JL, Felipe JS, Pral LP

Cell reports
27 2211-1247:750-761.e7 (2019)

PMID: 30995474

A SUV39H1-low chromatin state characterises and promotes migratory properties of cervical cancer cells.

Rodrigues C, Pattabiraman C, Vijaykumar A

Experimental cell research
1090-2422: (2019)

PMID: 30772380

Enzymatic Assays of Histone Decrotonylation on Recombinant Histones.

Fellows R, Varga-Weisz P

Bio-protocol
8 2331-8325: (2018)

PMID: 30283810

Chromatin remodeling: a collaborative effort.

Varga-Weisz PD

Nature structural & molecular biology
21 1545-9985:14-6 (2014)

PMID: 24389547

Keeping chromatin quiet: how nucleosome remodeling restores heterochromatin after replication.

JE Mermoud, SP Rowbotham, PD Varga-Weisz

Cell cycle (Georgetown, Tex.)
10 23:4017-25 (2011)

DOI: 10.4161/cc.10.23.18558

PMID: 22101266