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Hox in motion: tracking HoxA cluster conformation during differentiation.

ABSTRACT: Three-dimensional genome organization is an important higher order transcription regulation mechanism that can be studied with the chromosome conformation capture techniques. Here, we combined chromatin organization analysis by chromosome conformation capture-carbon copy, computational modeling and epigenomics to achieve the first integrated view, through time, of a connection between chromatin state and its architecture. We used this approach to examine the chromatin dynamics of the HoxA cluster in a human myeloid leukemia cell line at various stages of differentiation. We found that cellular differentiation involves a transient activation of the 5'-end HoxA genes coinciding with a loss of contacts throughout the cluster, and by specific silencing at the 3'-end with H3K27 methylation. The 3D modeling of the data revealed an extensive reorganization of the cluster between the two previously reported topologically associated domains in differentiated cells. Our results support a model whereby silencing by polycomb group proteins and reconfiguration of CTCF interactions at a topologically associated domain boundary participate in changing the HoxA cluster topology, which compartmentalizes the genes following differentiation.

SUBMITTER: Rousseau M

PROVIDER: S-EPMC3919592 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Hox in motion: tracking HoxA cluster conformation during differentiation.

Rousseau Mathieu M Crutchley Jennifer L JL Miura Hisashi H Suderman Matthew M Blanchette Mathieu M Dostie Josée J

Nucleic acids research 20131029 3

Three-dimensional genome organization is an important higher order transcription regulation mechanism that can be studied with the chromosome conformation capture techniques. Here, we combined chromatin organization analysis by chromosome conformation capture-carbon copy, computational modeling and epigenomics to achieve the first integrated view, through time, of a connection between chromatin state and its architecture. We used this approach to examine the chromatin dynamics of the HoxA cluste ...[more]

PMID: 24174538

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Project description:BackgroundHox genes are key elements in patterning animal development. They are renowned for their, often, clustered organisation in the genome, with supposed mechanistic links between the organisation of the genes and their expression. The widespread distribution and comparable functions of Hox genes across the animals has led to them being a major study system for comparing the molecular bases for construction and divergence of animal morphologies. Echinoderms (including sea urchins, sea stars, sea cucumbers, feather stars and brittle stars) possess one of the most unusual body plans in the animal kingdom with pronounced pentameral symmetry in the adults. Consequently, much interest has focused on their development, evolution and the role of the Hox genes in these processes. In this context, the organisation of echinoderm Hox gene clusters is distinctive. Within the classificatory system of Duboule, echinoderms constitute one of the clearest examples of Disorganized (D) clusters (i.e. intact clusters but with a gene order or orientation rearranged relative to the ancestral state).ResultsHere we describe two Hox genes (Hox11/13d and e) that have been overlooked in most previous work and have not been considered in reconstructions of echinoderm Hox complements and cluster organisation. The two genes are related to Posterior Hox genes and are present in all classes of echinoderm. Importantly, they do not reside in the Hox cluster of any species for which genomic linkage data is available.ConclusionIncorporating the two neglected Posterior Hox genes into assessments of echinoderm Hox gene complements and organisation shows that these animals in fact have Split (S) Hox clusters rather than simply Disorganized (D) clusters within the Duboule classification scheme. This then has implications for how these genes are likely regulated, with them no longer covered by any potential long-range Hox cluster-wide, or multigenic sub-cluster, regulatory mechanisms.

Project description:HOXA genes cluster plays a fundamental role in embryologic development. Deletion of the entire cluster is known to cause a clinically recognizable syndrome with mild developmental delay, characteristic facies, small feet with unusually short and big halluces, abnormal thumbs, and urogenital malformations. The clinical manifestations may vary with different ranges of deletions of HOXA cluster and flanking regions.We report a girl with the smallest deletion reported to date involving the entire HOXA cluster at 7p15.2-p14.3. The patient was the third child born to a healthy and non-consanguineous Italian couple. She was born at the 34th week of gestation by caesarean section due to cholestasis of pregnancy. Her birth weight, length, and occipitofrontal circumference were 2,140 g (25-50th centile), 46 cm (50th centile), and 33 cm (75-90th centile), respectively. The Apgar scores were 8 at both the 1st and 5th minutes. The patient presented with typical mild facial anomalies, hand and feet abnormalities, urinary anomalies, and mild speech delay. Unexpectedly, the patient demonstrated complex unusual features of multiple episodes of oxyhemoglobin desaturation, laryngeal stridor and a branchial cyst. Chromosome analysis of the patient revealed an apparently normal karyotype at the 550 band level. Based on array comparative genomic hybridization, a 2.5 Mb interstitial deletion was detected at 7p15.2p14.3 (chr7: 26,333,553-28,859,312), involving the entire HOXA cluster and a small number of other genes as SNX10, SKAP2, EVX1, HIBADH, TAX1BP1, JAZF1, and CREB5.This report improves our understanding of the genotype-phenotype correlations of HOXA genes cluster deletions via the identification and characterization of the smallest deletion (as well as critical region) reported to date. In particular we discuss the possible implications of preterm and haploinsufficiency in the pathogenesis of the unusual findings, furthermore opening new discussion and interpretation cues.

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Hox in motion: tracking HoxA cluster conformation during differentiation.

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Hox in motion: tracking HoxA cluster conformation during differentiation.

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