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Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD.

Mayes MB, Morgan T, Winston J, Buxton DS, Kamat MA, Smith D, Williams M, Martin RL, Kleinjan DA, Cooper DN, Upadhyaya M, Chuzhanova N - Hum. Genomics (2015)

Bottom Line: One of these variants was found to be of potential functional significance based on DNA methylation analysis.Further functional ascertainment will be required in order to establish the clinical/functional significance of the variants found.In this study, we propose an improved approach to predict the possible locations of remotely acting regulatory elements that might influence the transcriptional regulation of their associated gene(s).

View Article: PubMed Central - PubMed

Affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK.

ABSTRACT

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers.

Results: We identified two regions, located respectively ~14 and ~85 kb upstream of the SMCHD1 gene, which were then sequenced in 229 FSHD/FSHD-like patients (200 with D4Z4 repeat units <11). Three heterozygous sequence variants were found ~14 kb upstream of the SMCHD1 gene. One of these variants was found to be of potential functional significance based on DNA methylation analysis. Further functional ascertainment will be required in order to establish the clinical/functional significance of the variants found.

Conclusions: In this study, we propose an improved approach to predict the possible locations of remotely acting regulatory elements that might influence the transcriptional regulation of their associated gene(s). It represents a new way to screen for disease-relevant mutations beyond the immediate vicinity of the specific disease gene. It promises to be useful for investigating disorders in which mutations could occur in remotely acting regulatory elements.

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Related in: MedlinePlus

Pedigree (a) and mutation (b) in the proximal promoter region of the SMCHD1 gene, family 2
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Fig3: Pedigree (a) and mutation (b) in the proximal promoter region of the SMCHD1 gene, family 2

Mentions: We identified variants in the region proximal (~14 kb upstream) to the SMCHD1 gene in two probands from families 1 and 2. These variants were not present in dbSNP (http://www.ncbi.nlm.nih.gov/snp) or the 1000 Genomes Project data. The two variants, NCBI36/hg18:chr18:2,631,610 T > C and NCBI36/hg18:chr18:2,631,886 G > A, were found in probands from families 1 and 2, respectively (Figs. 2 and 3). They were also identified in the clinically unaffected mothers of these two patients.Fig. 2


Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD.

Mayes MB, Morgan T, Winston J, Buxton DS, Kamat MA, Smith D, Williams M, Martin RL, Kleinjan DA, Cooper DN, Upadhyaya M, Chuzhanova N - Hum. Genomics (2015)

Pedigree (a) and mutation (b) in the proximal promoter region of the SMCHD1 gene, family 2
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4597391&req=5

Fig3: Pedigree (a) and mutation (b) in the proximal promoter region of the SMCHD1 gene, family 2
Mentions: We identified variants in the region proximal (~14 kb upstream) to the SMCHD1 gene in two probands from families 1 and 2. These variants were not present in dbSNP (http://www.ncbi.nlm.nih.gov/snp) or the 1000 Genomes Project data. The two variants, NCBI36/hg18:chr18:2,631,610 T > C and NCBI36/hg18:chr18:2,631,886 G > A, were found in probands from families 1 and 2, respectively (Figs. 2 and 3). They were also identified in the clinically unaffected mothers of these two patients.Fig. 2

Bottom Line: One of these variants was found to be of potential functional significance based on DNA methylation analysis.Further functional ascertainment will be required in order to establish the clinical/functional significance of the variants found.In this study, we propose an improved approach to predict the possible locations of remotely acting regulatory elements that might influence the transcriptional regulation of their associated gene(s).

View Article: PubMed Central - PubMed

Affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK.

ABSTRACT

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers.

Results: We identified two regions, located respectively ~14 and ~85 kb upstream of the SMCHD1 gene, which were then sequenced in 229 FSHD/FSHD-like patients (200 with D4Z4 repeat units <11). Three heterozygous sequence variants were found ~14 kb upstream of the SMCHD1 gene. One of these variants was found to be of potential functional significance based on DNA methylation analysis. Further functional ascertainment will be required in order to establish the clinical/functional significance of the variants found.

Conclusions: In this study, we propose an improved approach to predict the possible locations of remotely acting regulatory elements that might influence the transcriptional regulation of their associated gene(s). It represents a new way to screen for disease-relevant mutations beyond the immediate vicinity of the specific disease gene. It promises to be useful for investigating disorders in which mutations could occur in remotely acting regulatory elements.

Show MeSH
Related in: MedlinePlus