enhancer

Epigenetic rewiring in Schinzel-Giedion syndrome

During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while some others can emerge in certain conditions, including other fate decisions or diseases, remains obscure. Schinzel-Giedion syndrome (SGS) is a rare disease with symptoms such as severe developmental delay, congenital malformations, progressive brain atrophy, intractable seizures, and infantile death. SGS is caused by mutations in the SETBP1 gene that results in its accumulation further leading to the downstream accumulation of SET. The oncoprotein SET has been found as part of the histone chaperone complex INHAT that blocks the activity of histone acetyltransferases suggesting that SGS may (i) represent a natural model of alternative chromatin regulation and (ii) offer chances to study downstream (mal)adaptive mechanisms. I will present our work on the characterization of SGS in appropriate experimental models including iPSC-derived cultures and mouse.

Dissecting the 3D regulatory landscape of the developing cerebral cortex with single-cell epigenomics

Understanding how different epigenetic layers are coordinated to facilitate robust lineage decisions during development is one of the fundamental questions in regulatory genomics. Using single-cell epigenomics coupled with cell-type specific high-throughput mapping of enhancer activity, DNA methylation and the 3D genome landscape in vivo, we dissected how the epigenome is rewired during cortical development. We identified and functionally validated key transcription factors such as Neurog2 which underlie regulatory dynamics and coordinate rewiring across multiple epigenetic layers to ensure robust lineage specification. This work showcases the power of high-throughput integrative genomics to dissect the molecular rules of cell fate decisions in the brain and more broadly, how to apply them to evolution and disease.

Cell Fate Determination in the Retina

The Cepko lab investigates the mechanisms that direct development of the central nervous system (CNS) of vertebrates, with a focus on the retina. These studies have revealed that the retina has distinct types of progenitor cells that are biased, or committed, to produce distinct types of daughter cells in terminal divisions. The gene regulatory networks that underlie these cell fate choices are being studied by analysis of both gene function and cis-regulatory networks. New methods that enable these studies have been developed, including high throughput enhancer assays and quantitative, inexpensive and sensitive multiplex in situ hybridization methods.

Two candidate K-Cl cotransporter 2 (KCC2) enhancers prevent epileptiform activity in vitro and in vivo

Development of a high-throughput phenotypic assay to screen for chemical enhancers of proteostasis activity in Caenorhabditis elegans

A far upstream enhancer is a crucial regulator of BDNF gene expression in rodent neurons and astrocytes

GT-02287, a clinical-stage GCase enhancer, improves activities of daily living and cognitive performance in a preclinical model of GBA1 Parkinson’s disease

FENS Forum 2024

Identification of sex-specific autophagy enhancers for dementia

FENS Forum 2024

A loss of spiral ganglion neurons with an active ATOH1 enhancer alters hearing function

FENS Forum 2024

An unbiased AAV-STARR-seq screen revealing the enhancer activity map of genomic regions in the mouse brain in vivo

FENS Forum 2024

Unlocking the role of Enhancer of Polycomb Homolog 1 (EPC1) in brain function

FENS Forum 2024