Differential abilities to engage inaccessible chromatin diversify vertebrate HOX binding patterns

Bulajić, Milica; Srivastava, Divyanshi; Js, Dasen; Wichterle, Hynek; Mahony, Shaun; Eo, Mazzoni

doi:10.1101/2019.12.29.890335

Cited by 13 publications

(22 citation statements)

References 76 publications

(80 reference statements)

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“…In the case of the Prox sequence a robust association was detected by CUT&RUN before an ATAC-seq peak could be scored, in support of the idea that HOX13 protein may in some instances display a pioneer effect (Bulajić et al, 2019;Desanlis et al, 2019).…”

Section: Hox13 Proteins Super-condensates and Pioneer Effectsupporting

confidence: 54%

A complex regulatory landscape involved in the development of mammalian external genitals

Amândio

Lopez-Delisle

Bolt

et al. 2020

eLife

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Developmental genes are often controlled by large regulatory landscapes matching topologically associating domains (TADs). In various contexts, the associated chromatin backbone is modified by specific enhancer–enhancer and enhancer–promoter interactions. We used a TAD flanking the mouse HoxD cluster to study how these regulatory architectures are formed and deconstructed once their function achieved. We describe this TAD as a functional unit, with several regulatory sequences acting together to elicit a transcriptional response. With one exception, deletion of these sequences didn’t modify the transcriptional outcome, a result at odds with a conventional view of enhancer function. The deletion and inversion of a CTCF site located near these regulatory sequences did not affect transcription of the target gene. Slight modifications were nevertheless observed, in agreement with the loop extrusion model. We discuss these unexpected results considering both conventional and alternative explanations relying on the accumulation of poorly specific factors within the TAD backbone.

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Section: Hox13 Proteins Super-condensates and Pioneer Effectsupporting

confidence: 54%

A complex regulatory landscape involved in the development of mammalian external genitals

Amândio

Lopez-Delisle

Bolt

et al. 2020

eLife

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Singh

Kumar

Paulson

et al. 2021

JDB

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Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in embryonic stem cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motif HB1RE (HOXB1 response element). In vitro template binding assays showed that HOXB1, PBX1, and MEIS can bind to this motif. In vivo, this motif is sufficient for direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novel HB1RE motif contributes to HOXB1 function in part through a repressive role in gene expression.

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“…This suggests that proximal cells may have acquired a more distal identity leading to a reduction in bone length. The recent observation that HOX13 proteins have a pioneer effect (Amândio et al, 2020; Bulajić et al, 2020; Desanlis et al, 2020) provides a potential mechanism for this to occur. On the other hand, in proximal cells ectopically expressing HOXD13, 70% of those sites are normally bound by HOXA11, which suggests that a large part of the change in proximal cells may result from interactions between HOXD13 and HOX11 proteins at these binding sites, potentially through the dominant negative effect of posterior prevalence.…”

Section: Discussionmentioning

confidence: 99%

MESOMELIC DYSPLASIAS ASSOCIATED WITH THEHOXDLOCUS ARE CAUSED BY REGULATORY REALLOCATIONS

Bolt

Lopez-Delisle

Mascrez

et al. 2021

Preprint

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Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same mechanism is responsible for this pathology in humans and mice. Amongst the proposed explanations, the various alterations to the genomic structure of HOXD could expose Hoxd13 to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. To assess this hypothesis, we used an engineered 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.

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Differential abilities to engage inaccessible chromatin diversify vertebrate HOX binding patterns

Cited by 13 publications

References 76 publications

A complex regulatory landscape involved in the development of mammalian external genitals

A complex regulatory landscape involved in the development of mammalian external genitals

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

MESOMELIC DYSPLASIAS ASSOCIATED WITH THEHOXDLOCUS ARE CAUSED BY REGULATORY REALLOCATIONS

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