第1182回生物科学セミナー

Nuclear microenvironments modulate transcription from low-affinity enhancers

Albert Tsai(Janelia Research Campus of the Howard Hughes Medical Institute, Ashburn, Virginia, USA)

2018年01月10日(Wed)    16:00-17:00  理学部3号館 327号室   

Transcription factors from the Homeobox (Hox) family pattern the anterior-posterior (head to tail) axis of all animals by acting as a master regulator for a host of downstream effector genes. However, as the family derived from a single ancestor gene, all members share similar binding site sequences. How animals can prevent them from cross-interacting with each other’s binding sites was an unresolved problem in developmental biology. Recent work discovered that low-affinity enhancers can differentiate between related Homeobox (Hox) transcription factors, leading to the correct body plan patterning during embryogenesis1. The same work also highlighted an inherent trade-off between binding site affinity and specificity: high affinity Hox binding sites that bind most members of the family tightly cannot discriminate between them.
However, transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. In collaboration with Justin Crocker2, we showed that the Hox transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogaster shavenbaby (svb) locus in nuclear microenvironments of high localized Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity of svb enhancers revealed an inverse relationship between enhancer affinity and Ubx concentration required for transcriptional activation. The Ubx cofactor, Homothorax (Hth), was co-enriched with Ubx near enhancers that require Hth, even though Ubx and Hth did not co-localize throughout the nucleus. Thus, microenvironments of high local transcription factor and cofactor concentrations could help low-affinity sites overcome their kinetic inefficiency. Mechanisms that generate these microenvironments could be a general feature of eukaryotic transcriptional regulation.
1. Crocker, J. et al. Low affinity binding site clusters confer hox specificity and regulatory robustness. Cell 160, 191–203 (2015).
2. Tsai, A. et al. Nuclear microenvironments modulate transcription from low-affinity enhancers. Elife 6, e28975 (2017).