In vivo Hox binding specificity revealed by systematic changes to a single cis regulatory module

Sánchez-Higueras, Carlos; Rastogi, Chaitanya; Voutev, Roumen; Bussemaker, Harmen J.; Mann, Richard S.; Hombría, James Castelli-Gair

doi:10.1038/s41467-019-11416-1

Cited by 33 publications

(48 citation statements)

References 37 publications

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“…Moreover, it is not surprising that many of the identified targets might be cell type-dependent, as several factors are known to contribute to the diversity and specificity of HOX protein activity, leading to highly dynamic, context-specific HOX transcriptional activation, and to their functional diversification. Indeed, it was described that i) there are many transcriptional partners -HOX cofactors and collaborators -that also present cell type-specific expression patterns [188,189]; ii) the binding between HOX proteins and their cofactors might be context-dependent [190], and different combinations may lead to distinct binding specificities, contributing to the spatiotemporal specificity of HOX proteins; and iii) chromatin accessibility and DNA shape, which may vary between cells, also showed to confer HOX specificity [191].…”

Section: Hoxd10mentioning

confidence: 99%

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

Gonçalves

Boiteux

Arnaud

et al. 2020

Cell. Mol. Life Sci.

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HOX genes encode a family of evolutionarily conserved homeodomain transcription factors that are crucial both during development and adult life. In humans, 39 HOX genes are arranged in four clusters (HOXA, B, C, and D) in chromosomes 7, 17, 12 and 2, respectively. During embryonic development, particular epigenetic states accompany their expression along the anterior-posterior body axis. This tightly regulated temporal-spatial expression pattern reflects their relative chromosomal localization, and is critical for normal embryonic brain development, when HOX genes are mainly expressed in the hindbrain and mostly absent in the forebrain region. Epigenetic marks, mostly polycombassociated, are dynamically regulated at HOX loci and regulatory regions to ensure the finely tuned HOX activation and repression, highlighting a crucial epigenetic plasticity necessary for homeostatic development. HOX genes are essentially absent in healthy adult brain, whereas they are detected in malignant brain tumours, namely gliomas, where HOX genes display critical roles by regulating several hallmarks of cancer. Here, we review the major mechanisms involved in HOX genes (de)regulation in the brain, from embryonic to adult stages, in physiological and oncologic conditions. We focus particularly on the emerging causes of HOX gene deregulation in glioma, as well as on their functional and clinical implications.

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Section: Hoxd10mentioning

confidence: 99%

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

Gonçalves

Boiteux

Arnaud

et al. 2020

Cell. Mol. Life Sci.

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“…Yet, the fact that a subset of HOX13 targets remain in an accessible chromatin state in Hox13-/-limb does not exclude the possibility that these targets could be switched to an accessible state by HOX13 in other cellular/tissue environments. Interestingly, a recent study investigating the in vivo HOX binding specificity at the vvl1+2 enhancer in Drosophila melanogaster suggests that HOX binding specificity relies on a combination of three parameters: binding specificity influenced by HOX cofactor(s), HOX monomers and interaction with collaborator proteins 23 . Our work reveals that the HOX13 pioneer activity, and possibly that of the other HOX factors, is one of the key parameters that specifies the HOX target repertoires.…”

mentioning

confidence: 99%

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

Desanlis

Kherdjemil

Mayran

et al. 2019

Preprint

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Hox genes encode essential transcription factors that control patterning during embryonic development. Distinct combinations of nested Hox expression domains establish cell and tissue identities 1-3 . Consequently, spatial or temporal de-regulation of Hox genes can cause severe alterations of the body plan 3 . While HOX factors have very similar DNA binding motifs, their binding specificity is, in part, mediated by co-factors 4-6 . Yet, the interplay between HOX binding specificities and the cellular context remains largely elusive. To gain insight into this question, we took advantage of developing limbs for which the differential expression of Hox genes is well-characterized 7 . We show that the transcription factors HOXA13 and HOXD13 (hereafter referred as HOX13) allow another HOX factor, HOXA11, to bind loci initially assumed to be HOX13-specific. Importantly, HOXA11 is unable to bind these loci in distal limbs lacking HOX13 function indicating that HOX13 modulates HOXA11 target repertoire.In addition, we find that the HOX13 factors implement the distal limb developmental program by triggering chromatin opening, a defining property of pioneer factors 8,9 . Finally, single cell analysis of chromatin accessibility reveals that HOX13 factors pioneer chromatin opening in a lineage specific manner. Together, our data uncover a new mechanism underlying HOX binding specificity, whereby tissue-specific variations in the target repertoire of HOX factors rely, at least in part, on HOX13-dependent chromatin accessibility.

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“…Although HOX homeodomain proteins were thought to function as transcription factors, most full-length HOX proteins, including HOXB6, bound only weakly to DNA targets containing a TAAT sequence, and the transcription of target genes was weakly activated or repressed ( Catron et al., 1993 ; Graba et al., 1997 ; Sánchez-Higueras and Rastogi, 2019 ). In addition, in one previous study, transient reporter gene analysis results revealed that HOXB6 and other HOX proteins did not change the activity of luciferase reporter vectors containing synthetic TAAT multimers or putative gene regulatory regions ( Shen et al., 2001 ).…”

Section: Discussionmentioning

confidence: 99%

MiR-126 Regulates Properties of SOX9+ Liver Progenitor Cells during Liver Repair by Targeting Hoxb6

Yan

Wang

et al. 2020

Stem Cell Reports

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Summary Liver progenitor cells (LPCs) have a remarkable contribution to the hepatocytes and ductal cells when normal hepatocyte proliferation is severely impaired. As a biomarker for LPCs, Sry-box 9 ( Sox9 ) plays critical roles in liver homeostasis and repair in response to injury. However, the regulation mechanism of Sox9 in liver physiological and pathological state remains unknown. In this study, we found that miR-126 positively regulated the expression of Sox9 , the proliferation and differentiation of SOX9 + LPCs by suppressing the translation of homeobox b6 ( Hoxb6 ). As a transcription factor, HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression, resulting in the destruction of the properties of SOX9 + LPCs in CCl 4 -induced liver injury. These findings revealed the role of miR-126 in regulating SOX9 + LPCs fate by targeting Hoxb6 in liver injury repair. Our findings suggest the potential role of miR-126 as a nucleic acid therapy drug target for liver failure.

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In vivo Hox binding specificity revealed by systematic changes to a single cis regulatory module

Cited by 33 publications

References 37 publications

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

MiR-126 Regulates Properties of SOX9+ Liver Progenitor Cells during Liver Repair by Targeting Hoxb6

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