Differential abilities to engage inaccessible chromatin diversify vertebrate HOX binding patterns

Abstract

While Hox genes encode for conserved transcription factors (TFs), they are further divided into anterior, central, and posterior groups based on their DNA-binding domain similarity. The posterior Hox group expanded in the deuterostome clade and patterns caudal and distal structures. We aim to address how similar HOX TFs diverge to induce different positional identities. We studied HOX TF DNA-binding and regulatory activity during an in vitro motor neuron differentiation system that recapitulates embryonic development. We find diversity in the genomic binding profiles of different HOX TFs, even among the posterior group paralogs that share similar DNA binding domains. These differences in genomic binding are explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 has a greater ability to bind occluded sites than the posterior HOXC10, producing different binding patterns and driving differential gene expression programs. From these results, we propose that the differential abilities of posterior HOX TFs to bind to previously inaccessible chromatin drive patterning diversification.

Ubx orchestrates tissue identity through regional and bidirectional changes to chromatin accessibility

“…Our ability to observe both increases and decreases in chromatin accessibility may be a consequence of studying the T2 versus T3 binary transformation, which includes multiple cell fates that are all modified by the presence of the same Hox protein. This is in contrast to previously characterized Hox-regulated systems, such as the vertebrate limb bud ( 27 ) or the induction of motor neuron fates from ESCs ( 26 ), where instead of transforming one tissue into another, Hox proteins promote the development of specific cell fates from less differentiated progenitors.…”

“…In addition to analyzing individual CRMs, the analysis of chromatin accessibility is a powerful approach to probe the mechanism by which gene regulatory networks are shaped by transcription factors, including Hox proteins ( 20–23 ). In insect cell culture, embryonic stem cells (ESC), and the mouse limb bud, Hox proteins can increase chromatin accessibility at specific loci in a paralog specific manner ( 24–26 ). For example the Hox proteins AbdB, HOXC9 and HOX13 paralogs (in Drosophila and mammals, respectively) have a relatively high capacity to bind inaccessible chromatin, whereas other Hox factors such as Ubx appear less able to do so and, consequently, are more restricted to binding chromatin that is already in an accessible conformation ( 24–27 ).…”

Genome-Wide Binding Analyses of HOXB1 Revealed a Novel DNA Binding Motif Associated with Gene Repression

“…The difference in preference for binding to accessible chromatin domains between HOXA1 and HOXB1 is interesting in light of recent findings demonstrating that several posterior HOX proteins display differences in their abilities to bind inaccessible chromatin sites [70]. This raises the possibility that HOXB1 may bind to inaccessible regions of chromatin and, in some cases, partner with PBX and MEIS to enhance chromatin accessibility and gene activity.…”

Role of HOXC10 in Cancer

“…Considerable evidence has shown that HOXC10 is closely related to mammalian physiological processes. Earlier studies reported that HOXC10 was involved in regulating anterior/posterior pattern specification ( 22 – 24 ), limb regeneration ( 25 – 27 ), and lumbar motor neuron differentiation ( 28 – 31 ). HOXC10 is also associated with angiogenesis ( 32 ), fat metabolism ( 33 – 38 ), and sex regulation ( 39 ).…”