Project Details
Description
Title: From 3D genomes to neural connectomes: Higher-order chromatin mechanisms encoding long-
term memory
Summary
The Cremins Lab focuses on higher-order genome folding and how classic epigenetic modifications work
through long-range, spatial mechanisms to govern genome function in the developing brain. Much is already
known regarding how transcription factors work in the context of the linear genome to regulate gene
expression. Yet, severe limitations exist in our ability to engineer chromatin in neural circuits to correct synaptic
defects in vivo. At the lab’s inception, it remained unclear whether and how genome folding would functionally
influence cell type-specific gene expression. Thus far, we have developed and applied new molecular and
computational technologies to discover that nested chromatin domains and long-range loops undergo marked
reconfiguration during neural lineage commitment, somatic cell reprogramming, neuronal activity stimulation,
and in repeat expansion disorders. We have demonstrated that loops induced by cortical neuron stimulation,
engineered through synthetic architectural proteins, and miswired in fragile X syndrome were tightly connected
to transcription, thus providing early insight into the genome’s structure-function relationship. We will now focus
on a fundamental mystery in neuroscience: how memory is encoded over decades despite rapid turnover of
synaptic proteins/RNAs. We hypothesize that the 3D genome integrates molecular traces of synaptic plasticity
written on chromatin to store long-term memory in neural circuits. We will employ single-cell genomics and
imaging technologies to dissect the extent to which individual synaptic inputs create 3D epigenetic traces. We
will perform genome-wide CRISPR screens to identify specific loops and epigenetic modifications functionally
important for synaptic plasticity. We will also re-direct technologies used for genome architecture mapping to
create molecular activity-dependent connectome maps, and computationally integrate neuronal connectome
maps across length scales with 3D epigenetic data sets. Successful completion of this work will shed new light
on the genetic and epigenetic mechanisms governing structural and functional synaptic plasticity in
physiologically relevant in vitro and in vivo models of memory encoding and consolidation. Many neurological
disorders exhibit synaptic defects, and alterations in neuronal activity-dependent gene expression underlie
pathological neural phenotypes. Addressing this knowledge gap will provide an essential foundation for our
long-term goals to understand how, when, and why pathologic genome misfolding leads to synaptic
dysfunction, and to engineer the 3D genome to reverse pathologic synaptic defects in debilitating neurological
diseases.
Status | Active |
---|---|
Effective start/end date | 8/15/21 → 7/31/24 |
Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH: $1,137,500.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $1,137,500.00
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