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Epigenetic control of cell identity
How chromatin controls cell identity
Every cell in the body carries essentially the same genome, yet a skin cell, a neuron and an embryonic stem cell behave in profoundly different ways. The answer lies in chromatin: the proteins and chemical modifications that package DNA and regulate which parts of the genome are accessible, active or silenced.
Our lab investigates how ATP-dependent chromatin remodellers — enzymes that position, slide or edit nucleosomes — control genome function and cell identity, and how defects in these mechanisms contribute to developmental disorders and disease.
Establishment and inheritance of transcriptional repression
How do cells establish gene and repeat silencing, reshape it during differentiation and preserve it through successive cell divisions? We investigate how DNA methylation, histone modifications and chromatin remodellers cooperate to regulate these processes, which are essential for maintaining cell identity and genome stability.
Using mouse embryonic stem cells and human keratinocytes, we study these mechanisms at retrotransposons, pericentric heterochromatin and the inactive X chromosome. Our work identified SMARCAD1 as a chromatin remodeller that mediates transcriptional repression; its loss leads to the de-repression of endogenous retroviruses and nearby genes. We are now dissecting the underlying mechanisms to understand how chromatin remodelling contributes to stable transcriptional silencing.
Chromatin remodelling in human skin
What happens to the epidermis when a chromatin remodeller fails? Mutations affecting the skin-specific isoform of SMARCAD1 cause a spectrum of rare inherited disorders: adermatoglyphia, Huriez syndrome and Basan syndrome. These conditions affect epidermal development and homeostasis; Huriez syndrome is particularly notable for its markedly increased risk of cutaneous squamous cell carcinoma.
We have shown that disease-causing variants act through haploinsufficiency and that SMARCAD1 dosage is tightly controlled even in healthy cells. By investigating SMARCAD1 function in normal keratinocytes and in ectodermal disorders, we aim to understand how chromatin remodelling supports epidermal integrity and how its disruption can contribute to cancer predisposition.
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