Abstract
BackgroundThe product of dosage compensation in female mammals is the inactive X chromosome (Xi). Xi facultative heterochromatin is organized into two different types, one of which is defined by histone H3 trimethylated at lysine 9 (H3K9me3). The rationale for this study was to assess SET domain bifurcated 1 (SETDB1) as a candidate for maintaining this repressive modification at the human Xi.ResultsHere, we show that loss of SETDB1 does not result in large-scale H3K9me3 changes at the Xi, but unexpectedly we observed striking decompaction of the Xi territory. Close examination revealed a 0.5 Mb region of the Xi that transitioned from H3K9me3 heterochromatin to euchromatin within the 3′ end of the IL1RAPL1 gene that is part of a common chromosome fragile site that is frequently deleted or rearranged in patients afflicted with intellectual disability and other neurological ailments. Centrally located within this interval is a powerful enhancer adjacent to an ERVL-MaLR element. In the absence of SETDB1, the enhancer is reactivated on the Xi coupled with bidirectional transcription from the ERVL-MaLR element. Xa deletion of the enhancer/ERVL-MaLR resulted in loss of full-length IL1RAPL1 transcript in cis, coupled with trans decompaction of the Xi chromosome territory, whereas Xi deletion increased detection of full-length IL1RAPL1 transcript in trans, but did not impact Xi compaction.ConclusionsThese data support a critical role for SETDB1 in maintaining the ERVL-MaLR element and adjacent enhancer in the 3′ end of the IL1RAPL1 gene in a silent state to facilitate Xi compaction.
Highlights
The product of dosage compensation in female mammals is the inactive X chromosome (Xi)
H3K27me3 is catalyzed by the histone methyltransferase (HMTase) enhancer of Zeste 2 (EZH2) [10,11,12,13], which applies the mark to chromatin of the Xi early during X chromosome inactivation (XCI) [4, 5]
SET domain bifurcated 1 (SETDB1) loss results in decompaction of the territory of the Xi In order to knock out SETDB1, we used the fast ligationbased automatable solid-phase high-throughput system (FLASH) to assemble a pair of previously reported active transcription activator-like effector nuclease (TALENs) that target exon-2 (Fig. 1a) of the SETDB1 locus [21]
Summary
The product of dosage compensation in female mammals is the inactive X chromosome (Xi). The rationale for this study was to assess SET domain bifurcated 1 (SETDB1) as a candidate for maintaining this repressive modification at the human Xi. The XX/XY chromosome mode of sex determination necessitates the need to compensate levels of X-linked gene expression between the sexes. The XX/XY chromosome mode of sex determination necessitates the need to compensate levels of X-linked gene expression between the sexes In mammals, this is achieved through the process of X chromosome inactivation (XCI), whereby one of the two X chromosomes in females is rendered transcriptional silent early in development [1]. Gene silencing at the inactive X chromosome (Xi) is achieved by repackaging the chromosome into facultative heterochromatin, which includes acquisition of repressive histone marks such as histone H3 methylated at lysine 9 and trimethylated at lysine 27 (H3K27me3) [2,3,4,5]. Recent data suggest that SET domain bifurcated 1 (SETDB1), an H3-K9 HMTase with highest activity for trimethylation of lysine 9 [16, 17], is involved in maintaining gene silencing on
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