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Thoughts about SLC16A2, TSIX and XIST gene like sites in the human genome and a potential role in cellular chromosome counting
© The Author(s). 2016
Received: 6 July 2016
Accepted: 25 July 2016
Published: 8 August 2016
Chromosome counting is a process in which cells determine somehow their intrinsic chromosome number(s). The best-studied cellular mechanism that involves chromosome counting is ‘chromosome-kissing’ and X-chromosome inactivation (XCI) mechanism. It is necessary for the well-known dosage compensation between the genders in mammals to balance the number of active X-chromosomes (Xa) with regard to diploid set of autosomes. At the onset of XCI, two X-chromosomes are coming in close proximity and pair physically by a specific segment denominated X-pairing region (Xpr) that involves the SLC16A2 gene.
An Ensembl BLAST search for human and mouse SLC16A2/Slc16a2 homologues revealed, that highly similar sequences can be found at almost each chromosome in the corresponding genomes. Additionally, a BLAST search for SLC16A2/TSIX/XIST (genes responsible for XCI) reveled that “SLC16A2/TSIX/XIST like sequences” cover equally all chromosomes, too. With respect to this we provide following hypotheses.
If a single genomic region containing the SLC16A2 gene on X-chromosome is responsible for maintaining “balanced” active copy numbers, it is possible that similar sequences or gene/s have the same function on other chromosomes (autosomes). SLC16A2 like sequences on autosomes could encompass evolutionary older, but functionally active key regions for chromosome counting in early embryogenesis. Also SLC16A2 like sequence on autosomes could be involved in inappropriate chromosomes pairing and, thereby be involved in aneuploidy formation during embryogenesis and cancer development. Also, “SLC16A2/TSIX/XIST gene like sequence combinations” covering the whole genome, could be important for the determination of X:autosome ratio in cells and chromosome counting.
SLC16A2 and/or SLC16A2/TSIX/XIST like sequence dispersed across autosomes and X-chromosome(s) could serve as bases for a counting mechanism to determine X:autosome ratio and could potentially be a mechanism by which a cell also counts its autosomes. It could also be that such specific genomic regions have the same function for each specific autosome. As errors during the obviously existing process of chromosome counting are one if not the major origin of germline/somatic aneuploidy the here presented hypotheses should further elaborated and experimentally tested.
SLC16A2 like sequences on autosomes could be and/or encompass the evolutionary older, but functionally active key regions for chromosome counting in early embryogenesis.
If a single genomic region containing the SLC16A2 gene is responsible for maintaining “balanced” copy numbers of only one Xa, it is possible that similar sequences or gene/s have the same function for other chromosomes (autosomes); the similarity or homology of these sequences in the genome could be involved in inappropriate chromosomes pairing [18, 19].
“SLC16A2/TSIX/XIST like sequence combinations” are covering the whole human and murine genome, making it plausible that this combination is important for determination of X:autosome ratio in cells and for chromosome counting.
Discussion and conclusion
Early studies on XCI have been conducted without complete knowledge of human genomic sequences, and as elaborated before, all efforts for finding the “counting region” was focused on a small part of the XIC region. Mechanisms of XCI were extensively studied as early as in 1990. Riggs  put forward the idea that along the X-chromosome there are “way station” or “boosters” elements that are facilitating inactivation speeding on the X-chromosome . Furthermore, studies on X:autosome translocation and Xist yeast artificial chromosome (YAC) transgenes of the autosome showed that inactivation can spread and silence autosomal genes, too [21, 22]; this was also shown in clinical cases . The inactivation is not as efficiently as inactivation of genes on X-chromosome and it can vary from autosome to autosome. Thus, it was evident that sequence(s) involved in spreading of inactivation is/are not specific to X-chromosomal sequences. Further studies on individual autosomal trisomic female cases showed that XCI is not altered (one Xi and one Xa), while two Xa featured the majority of triploid female embryos [24, 25]. During early years of genetics it was generally assumed that a core of Xi or Barr body was made up from silenced X-chromosomal genes, but 2D and 3D architecture studies revealed higher-level organization of Xi. In general most of the genes (regardless of activity and position on the metaphase chromosome) are arranged in the periphery of the Xi, and most of the noncoding and repetitive sequence reside within the interior of Xi .
In summary, facts about X-chromosome counting and XCI are: (i) there is one Xa per diploid set of autosomes in mammalian cells; (ii) before XCI, early in embryogenesis, cells are capable to count chromosomes and to determinate the X:autosome ratio; (iii) on the onset of embryogenesis two (or more) X-chromosomes come in close proximity; (iv) there is a higher-level organization of the Xi (in general noncoding and repetitive sequences inside, while genes are positioned outside). Regarding (iii) and (iv), two opposite “phenomena” were discovered: chromosome territories and chromosome kissing. First one describes how in a nucleus chromosomes are occupying distinct and well-defined territories [27, 28]. The “phenomenon” of two chromosomes coming close together or “chromosome kissing” referrers to inter-chromosomal interactions between pairs of chromosomes or specific parts of them .
Chromosome and gene positioning in the nucleus is clearly important for numerous functions. Among others, chromosome counting could be one of the cellular processes that requires specific nucleus architecture in a sense that X-chromosome/s is/are in contact with autosomes.
Sequence similarity across autosomes and X-chromosome(s) could serve as counting mechanism to determine X:autosome ratio, and it could be that some specific genomic regions have the same function for each autosome, too. Consequently, errors during chromosome counting could be the first step in formation of chromosomal aneuploidies during embryogenesis and cancer development. SLC16A2/TSIX/XIST gene like sequence combinations cover the whole genome; thus it may be speculated that they could serve as such check points. Sequence similarities across autosomes and X-chromosome(s) could be prerequisite for pairing and counting mechanisms.
Interestingly, when comparing human and murine X-chromosomes and SLC16A2/Slc16a2 genes localized there, one finds that they have different transcription directions (Fig. 4). If this is meaningful in any way has to be ruled out be further studies. However, it once again raises additional questions about the suitability of mouse as a model for human.
Overall, supportive facts for the here presented hypothesis are that chromosome kissing/counting is important for (i) regulation of gene expression (silencing and activation); (ii) tissue specific transcription; (iii) cell fate and (iv) DNA replication control [19, 29–32]. However, the onset of XCI is most likely not the only example of chromosome kissing. Accordingly, it seems to be necessary to carry out a more generalized search for sequences driving inter-chromosomal interactions. SLC16A2/TSIX/XIST gene like sequence may have to be more in focus of research here.
2D and 3D, two and three dimensional; BAC, bacterial artificial chromosomes; BAC FISH, fluorescence in situ hybridization using bacterial artificial chromosomes; BLAST, basic local alignment search tool; DNA, deoxyribonucleic acid; LINE, long interspersed elements; RNA, ribonucleic acid; Xa, active X-chromosome; XCI, X-chromosome inactivation; Xi, inactive X-chromosome; XIC, X inactivation center; Xpr, X-pairing region; YAC, yeast artificial chromosomes
Ivan Y Iourov is supported by the Russian Science Foundation (project #14-35-00060) at Moscow State University of Psychology and Education.
Ivan Y Iourov is supported by the Russian Science Foundation (project #14-35-00060) at Moscow State University of Psychology and Education. This had no influence in the design of the study and collection, analysis, and interpretation of data.
Availability of data and materials
TL and MR developed the hypotheses. MR did the detailed literature search and database analyses, drafted the paper, and drated the figures. IYI and TL finished the paper draft and developed together with MR the details of the hypotheses. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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