HOX and Patterning
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How does a DNA sequence decode a transient signal and store it as a permanent memory?
During cell differentiation, early progenitor cells receive transient signals that remain through cell generations and impact later stages of differentiation. Understanding how epigenetic memory is established and stored is crucial for understanding cell differentiation and disease. The positional identity determined by Hox genes is the quintessential example of epigenetic memory. Proper Hox genes expression is critical for development and is dysregulated in numerous diseases, including cancer. With a novel synthetic DNA technology, we recently showed that epigenetic memory is self-contained within the unusually compact and conserved Hox clusters. Using this, we aim to answer a longstanding question: how does a 100 kilobase genomic fragment containing 10 Hox genes translate a transient signal into stable positional epigenetic memory?
Schematic of HoxA regulation in response to retinoic acid (RA) during in vitro mouse ES cell (mESC)-motor neuron differentiation and our approach for synthetic regulatory reconstitution. See more at Pinglay et al., Science 2022.
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How do similar transcription factors with identical DNA motifs drive different cell fates?
Transcription factors (TFs) are important regulators of cell identity. By recognizing short DNA motifs, they are directed to specific sites in the genome from where they regulate the expression of their target genes. Different TFs recognize different DNA motifs and regulate distinct sets of target genes, thus driving different cellular fates. However, we currently do not understand how similar TFs that recognize identical DNA motifs can contribute to the cell type diversity encountered in multicellular organisms.
Posterior HOX TFs are a good model to understand how similar TFs diversify to fulfil unique biological functions, as they are derived from a single common ancestor and recognize identical DNA motifs, yet drive distinct cellular identities during development. To achieve our goal of understanding the molecular mechanisms that underlie the diversification of posterior HOX TFs, we are combining differentiation protocols with genome-wide assays and advanced fluorescence microscopy.
Single molecular tracking of HALO-tagged Hox transcription factors