Elucidating the function of the autism risk gene CTCF in neural differentiation-dependent chromatin organization
- Awarded: 2024
- Award Type: Pilot
- Award #: SFI-AN-AR-Pilot-00005960
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by a wide range of cognitive and behavioral alterations. The etiology of ASD remains elusive, with genetic and epigenetic factors playing crucial roles in its pathogenesis. Recent advances in genomics have provided valuable insights into the role of dynamic chromatin reorganization during brain development and what happens when these processes go awry in neurodevelopmental conditions.
CTCF was recently identified as a high-confidence ASD risk gene that encodes a key protein involved in global chromatin organization. It plays a pivotal role in regulating gene expression by facilitating long-range chromatin interactions. However, the precise mechanisms by which CTCF contributes to neural differentiation-dependent chromatin organization and ASD pathogenesis are poorly understood.
Preliminary data from Hiruy Meharena’s lab indicate that CTCF is a critical regulator of the dynamic transcriptional changes that occur during neural differentiation. In the current project, Meharena and his team aim to elucidate the function of CTCF by studying the molecular and cellular consequences of two ASD-associated CTCF mutations in human pluripotent stem cells (hPSCs), hPSC-derived neural progenitor cells (NPCs) and NPC-derived neural organoids. They plan to use state-of-the-art chromatin conformation capture techniques such as PLAC-seq (proximity ligation-assisted chromatin immunoprecipitation sequencing [ChIP-Seq])1, HiChIP (a protein-centric chromatin conformation method)2, and lamina-associated domain mapping to examine the role of CTCF in shaping neural differentiation-dependent long-range chromatin interactions and nuclear architecture. They also plan to investigate the impact of CTCF mutations on neural differentiation, maturation and function.
By uncovering the role of CTCF in neural differentiation-dependent chromatin organization, the researchers hope to identify potential mechanisms that contribute to the development of ASD. Such knowledge may ultimately offer insights into targeted therapies and diagnostic tools for this complex condition.