Biology subjects

Monahan, K.

Publications and source records attributed to Monahan, K..

3 recordsLinked to original sources

bioRxiv2018

Ldb1 mediates trans enhancement in mammals

Singular olfactory receptor (OR) gene expression1,2 coincides with the formation of a multi-chromosomal enhancer hub that associates with the only transcribed OR allele in each cell3,4. This hub consists of converging transcriptional enhancers3, or \"Greek Islands\", defined by stereotypic binding of Lhx2 and Ebf on a shared, composite DNA motif5. How this multi-chromosomal hub, or any other genomic compartment, assembles is unknown, and so is the significance of compartmentalization in transcription. Here, we report that LIM domain binding protein 1 (Ldb1), which is recruited by Lhx2 and Ebf to Greek Islands, promotes robust and specific trans interactions between these enhancers. In addition to disrupting Greek Island hubs, Ldb1 deletion also causes significant downregulation of OR transcription. Thus, our data provide insight to the formation of genomic compartments, confirm the essential role of interchromosomal interactions in OR gene choice, and establish trans enhancement as a mechanism for mammalian gene activation.

genomics↗

bioRxiv2018

Cell type-specific interchromosomal interactions as a mechanism for transcriptional diversity

The eukaryotic genome is partitioned into topologically associated domains (TADs) that assemble into compartments of shared chromatin valance. This architecture is influenced by the physical constraints imposed by the DNA polymer, which restricts DNA interactions predominantly to genomic segments from the same chromosome. Here, we report a dramatic divergence from this pattern of nuclear organization that occurs during the differentiation and specification of mouse olfactory sensory neurons (OSNs). In situ HiC on FAC-sorted OSNs shows that olfactory receptor (OR) genes from numerous chromosomes make frequent, extensive, and highly specific interchromosomal contacts that strengthen with differentiation. Moreover, in terminally differentiated OSNs, >30 intergenic enhancers generate a multi-chromosomal hub that associates only with the single active OR from a pool of [~]1400 genes. Our data reveal that interchromosomal interactions can form with remarkable stereotypy between like neurons, generating a regulatory landscape for stochastic, monogenic, and monoallelic gene expression.

genomics↗

bioRxiv2017

Cooperative Interactions Enable Singular Olfactory Receptor Expression

The monogenic and monoallelic expression of only one out of > 1000 olfactory receptor (ORs) genes requires the formation of large heterochromatic chromatin domains that sequester the OR gene clusters. Within these domains, intergenic transcriptional enhancers evade heterochromatic silencing and converge into interchromosomal hubs that assemble over the transcriptionally active OR. The significance of this nuclear organization in OR choice remains elusive. Here, we show that transcription factors Lhx2 and Ebf specify OR enhancers by binding in a functionally cooperative fashion to stereotypically spaced motifs that defy heterochromatin. Specific displacement of Lhx2 and Ebf from OR enhancers resulted in pervasive, long-range, and trans downregulation of OR transcription, whereas pre-assembly of a multi-enhancer hub increased the frequency of OR choice in cis. Our data provide genetic support for the requirement and sufficiency of interchromosomal interactions in singular OR choice and generate general regulatory principles for stochastic, mutually exclusive gene expression programs.

neuroscience↗