top of page

Our Research

Our research lies at the intersection of three primary domains: transcriptional enhancers, stem cells, and cancer.

Regulation of cellular metabolism and epigenome downstream of FGF/ERK signalling in stem cells


Transcriptional enhancers, vital non-coding genomic elements, translate intercellular signals into specific transcriptional responses, ultimately determining cell identity crucial for proper organismal development. Despite their significance, our knowledge about enhancer regulation downstream of cell signalling in gene regulation remains limited. The impact of alterations in cellular metabolism on the epigenetic marking of enhancers in response to cell signalling remains poorly understood. We recently discovered an epigenetic axis involving the transcription factor Spic, 1C metabolism, and histone arginine methylation that operates downstream of FGF signalling in ESCs (Mirzadeh Azad et al, Science Advances 2023). We show that Spic activates the one-carbon metabolism, resulting in lower SAM/SAH levels and H3R17me2a, a crucial histone mark linked to pluripotency. In this research project, we investigate the precise molecular steps underlying this pathway, bridging the gap between cellular metabolism and epigenetic regulation in stem cells.

transcription factor spic is activated downstream of ERK/MEK influences 1C metabolism, reduces sam/sah level and affect histone methylation

Unravelling the molecular mechanisms linking WNT Signalling and chromatin regulation in stem cells


‘WNTs’ are key signalling molecules communicated between cells that play cardinal roles in normal development. WNT-signalling is an ancient way that many species use to instruct tissue formation in the developing embryo and in adult tissues. Given its importance, it is not surprising that WNT-signalling is also one of the top activated signalling pathways in cancer. However, there is still a fundamental gap in our knowledge about the molecular steps by which WNT signals are transmitted to DNA to turn ON and OFF gene expression. Understanding these mechanisms is crucial for understanding normal development, tissue regeneration and cancer in which WNT signals play a driver role. We recently discovered that WNT signals can tag certain chromatin proteins (such as the CHD4-NuRD complex) by a specific chemical modification called ‘phosphorylation’.  In addition, we have found that when these proteins are phosphorylated, they show different activities. In this research project we explore the molecular mechanisms by which phosphorylation of specific chromatin proteins regulates gene expression and cellular identity in response to WNT signals in stem cells.

WNT activates chd4 by influencing its phosphorylation through GSK3

The role of USP7-PRC1.6-H2AK119Ub epigenetic axis in cancer


Chromatin regulation is important for controlling cell identity in normal tissues and is often deregulated in cancer leading to uncontrolled gene expression. We recently discovered that a specific protein complex called USP7-PRC1.6 increases the level of a specific chemical modification called H2AK119Ub at chromatin (Sijm and Atlasi et al, Science Advances 2022). We also found that this molecular mechanism is important for turning off gene expression. These observations lead us to hypothesize that USP7-PRC1.6-H2Ak119Ub plays an important role in controlling cell identity. In this research project, we aim to explore the molecular mechanisms by which USP7-PRC1.6 controls cellular identity in healthy intestine and in colorectal cancer. Furthermore, we investigate the involvement of the newly discovered USP7-PRC1.6-H2AK119UB epigenetic axis in chemotherapy resistance within cancer cells, with particular focus on colorectal cancer and Non-Hodgkin Lymphomas.

USP7 controls PRC1 and promotes H2a119ub

Deciphering the epigenetic basis of drug resistance in colorectal cancer


Treatment with 5-fluorouracil (5FU)-based chemotherapy is the main option for most colorectal cancer (CRC) patients. However, chemotherapy resistance remains a major hurdle in CRC treatment. Recent discoveries highlight a remarkable similarity between chemo-resistant cancer cells and cells found in the early embryo, suggesting that cancer cells can hijack a range of stem, and embryonic programmes to enter a dormant state that enables them to survive treatment. This drug resistance-persistence state is associated with reversible epigenetic reprogramming allowing cells to reinitiate tumour growth upon drug release.  In this project, we aim to identify the reversible epigenetic changes underpinning cell plasticity in response to 5FU treatment, with a particular focus on transcriptional enhancers and the role of the PRC1/2 complexes. Better understanding of these epigenetic mechanisms will provide new therapeutic approaches to prevent or overcome drug resistance in cancer.

colorectal cancer
resistance to chemptherapy in CRC

Functional dissection of the role of polymorphisms in non-coding genome in cancer


Germline polymorphisms and somatic mutations within the non-coding genome can significantly impact both the activity of transcriptional enhancers and the 3D genome organization. In collaboration with Dr. Nick Orr from the PGJCCR at QUB, we are undertaking a project aimed at studying the functional aspects of germline polymorphisms at 14q24 and their influence on predisposition to breast cancer. Utilizing functional genomic approaches, we investigate how these polymorphisms affect regulatory elements, ultimately leading to transcriptional changes in candidate genes associated with cancer.

bottom of page