The Stadtfeld laboratory
Core interests and approaches
Our laboratory studies the molecular mechanisms by which signaling pathways, transcription factors, and chromatin regulators interact to establish distinct gene expression programs and unique cell states during human development. We use pluripotent stem cells to reconstruct key stages of embryogenesis in a tractable manner, with a particular focus on nervous system and gut development. By combining precise genome engineering with temporally controlled protein perturbation, functional genomics, epigenome profiling, and single-cell approaches, we capture and dissect gene-regulatory mechanisms during dynamic developmental processes with high temporal and cellular resolution.
Chromatin regulation in human neurodevelopment
Mutations in chromatin regulators are major genetic causes of neurodevelopmental disorders, yet many of the affected proteins are broadly expressed. We seek to understand how ubiquitous chromatin regulators acquire specific functions across developmental trajectories and cell types, and why alterations in their levels or activity selectively affect neural development.
A major focus are repressive histone methyltransferases such as EHMT1, whose haploinsufficiency causes Kleefstra syndrome and is associated with autism and intellectual disability. Using human stem cell models of cortical neurogenesis, we investigate how EHMT1 and other broadly expressed chromatin regulators are recruited to specific genomic regions, how their functions change during development, and when they are required for faithful neuronal differentiation. By removing and restoring gene regulatory proteins at defined developmental stages, we also ask how reversible the molecular consequences of their loss are.
Transcriptional interpretation of developmental signals
The same developmental signal can produce very different outcomes depending on when and where it is received. We investigate how a developing cell's transcriptional and epigenetic state determines its response to specific extracellular cues.
Our work focuses particularly on the interplay between WNT signaling and the patterning transcription factor OTX2 during early human brain and gut development. By controlling signaling activity and transcription factor function during defined developmental transitions, we investigate how signaling effectors and transcription factors cooperate at enhancers and other regulatory elements to generate context-specific transcriptional responses and regional cell identities.
Ultimately, our work aims to uncover regulatory principles that underlie human development and to investigate how this understanding might be harnessed therapeutically to ameliorate or cure developmental disorders.