Pombo Lab · Baltimore · Berlin

Epigenetic regulation and chromatin architecture

Our group is interested in understanding the interplay between gene regulation and genome architecture, towards defining rules and principles of genome function.

About the lab

We study mechanisms of gene expression at multiple levels, from the local action of transcription factors, to long-range chromatin looping events that connect regulatory DNA sequences with the genes they regulate, to how whole chromosomes are positioned within cell nuclei. Binding of transcription factors at regulatory sequences helps recruit chromatin remodelers and the transcription machinery to transcription sites.

Upon recruitment, RNA polymerases either remain primed for subsequent activation (e.g. after environmental stress, during differentiation or disease), or directly transcribe the DNA template into RNA molecules, which code for proteins or for structural RNAs that constitute many enzymatic complexes.

An increasingly important aspect of gene regulation is the three-dimensional folding of the genome, and the mechanisms that control physical contacts of distant regulatory DNA sequences with gene promoters to activate gene expression. To directly measure genome topologies, our group developed Genome Architecture Mapping (GAM).

Our long-term strategy for unravelling the principles of genome function in higher eukaryotes aims to integrate multiple parameters, which is becoming increasingly possible with state-of-the-art developments in single cell genomics, molecular biology, epigenetics, nuclear imaging, and genetics.

Our main goal is to unravel the diverse mechanisms of mammalian gene regulation and their roles in development and disease. Gene activation is controlled locally through transcription factors, chromatin modifiers, and the transcription and RNA processing machineries. Gene expression is also intricately regulated by the three-dimensional (3D) structure of the genome, which modifies the location of genes relative to activating or repressing biochemical environments. Repressing nuclear locations include the nuclear lamina and heterochromatin. Activating 3D genome conformations can work by regulating the physical proximity between regulatory regions and their responsive genes. As many disease-associated genetic variants fall in non-coding regulatory elements scattered in the genome, our work aims to advance the functional interpretation of the linear genome sequence. We especially put effort in devising experimental and computational approaches to map 3D genome structure in different cell types, in development and in disease, to study developmental and disease mechanisms, towards novel diagnostics, prognostics and therapeutics.

Selected Publications

Extensive folding variability between homologous chromosomes in mammalian cells
Irastorza-Azcarate, I., Kukalev, A., Kempfer, R., Thieme, C. J., Mastrobuoni, G., et al.
Molecular Systems Biology, 2025
Multiplex-GAM: genome-wide identification of chromatin contacts yields insights overlooked by Hi-C
Beagrie, R. A., Thieme, C. J., Annunziatella, C., Baugher, C., Zhang, Y., et al.
Nature Methods, 2023
Complex multi-enhancer contacts captured by genome architecture mapping
Beagrie, R. A., Scialdone, A., Schueler, M., Kraemer, D. C. A., Chotalia, M., Xie, S. Q., et al.
Nature, 2017
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