Monoallelic Gene Expression (MAE): phenomenon of the gene expression, when only one of the two gene copies (alleles) is actively expressed (transcribed) , while the other is silent.
Diploid organism bears two homologous copies of each chromosome (one from each parent), a gene can be expressed from both chromosomes (biallelic
expression) or from only one (monoallelic expression).
MAE can be random (RME) or deterministic (constitutive).
Constitutive monoallelic expression occurs from the same specific allele throughout the whole organism or tissue, as a result of genomic imprinting[1].
Random monoallelic expression (RME) is a broader class of monoallelic expression, which is defined by random allelic choice in somatic cells, so that different cells of the multi-cellular organism express different alleles.
Constitutive monoallelic gene expression
editRandom monoallelic gene expression (RME)
editX-chromosome inactivation (XCI), is the most striking ans well-studied example of RME. XCI leads to the transcriptional silencing of one of the X chromosomes in female cells, which results in expression of the genes that located on the other, remaining active X chromosome. XCI is critical for balanced gene expression in female mammals. The allelic choise of XCI by individual cells takes place randomly in epiblasts of the preimplantation embryo[2], which leads to mosaic gene expression of the paternal and maternal X chromosome in female tissues [3][4]. XCI is a chromosomme-wide monoallelic expression, that includes expression of all genes that are located on X chromosome, in contrast to autosomal RME (aRME) that relates to single genes that are interspersed over the genome. aRMEs can be fixed[5] or dynamic, depending whether or not the allele-specific expression is conserved in daughter cells after mitotic cell division.
Types of aRME
editFixed aRME are established either by silencing of one allele that previously has been biallelically expressed, or by activation of a single allele from previously silent gene. Expression activation of the silent allele is coupled with a feedback mechanism that prevents expression of the second allele. Another scenario is also possible due to limited time-window of low-probability initiation, that could lead to high frequencies of cells with single-allele expression. It is estimated that 2[6][7]-10[8]% of all genes are fixed aRME. Studies of fixed aRME require either expansion of monoclonal cultures or lineage-traced in vivo or in vitro cells that are mitotically.
Dynamic aRME occurs as a consequence of stochastic allelic expression. Transcription happens in bursts, which results in RNA molecules being synthesized from each allele separately. So over time, both alleles have a probability to initiate transcription. Transcriptional bursts are allelically stochastic, and lead to either maternal or paternal allele being accumulated in the cell. The gene transcription burst frequency and intensity combined with RNA-degradation rate form the shape of RNA distribution at the moment of observation and thus whether the gene is bi- or monoallelic. Studies that distinguish fixed and dynamic aRME require single-cell analyses of clonally related cells[9].
Mechanisms of aRME
editAllelic exclusion is a process of gene expression when one allele is expressed and the other one kept silent. Two most studied cases of allelic exclusion are monoallelic expression of immunoglobulins in B and T cells[10][11][12] and olfactory receptors in sensory neurons[13]. Allelic exclusion is cell-type specific (as opposed to organism-wide XCI), which increases intercellular diversity, thus specificity towards certain antigens or odors.
Allele-biased expression is skewed expression level of one allele over the other, but both alleles are still expressed (in contrast to allelic exclusion). This phenomenon is often observed in cells of immune function[14][15].
Methods of detection
editReferences
edit- ^ Garfield, AS; Cowley, M; Smith, FM; Moorwood, K; Stewart-Cox, JE; Gilroy, K; Baker, S; Xia, J; Dalley, JW; Hurst, LD; Wilkinson, LS; Isles, AR; Ward, A (27 January 2011). "Distinct physiological and behavioural functions for parental alleles of imprinted Grb10". Nature. 469 (7331): 534–8. doi:10.1038/nature09651. PMID 21270893.
- ^ Monk, M; Harper, MI (27 September 1979). "Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos". Nature. 281 (5729): 311–3. PMID 551278.
- ^ Hadjantonakis, AK; Cox, LL; Tam, PP; Nagy, A (March 2001). "An X-linked GFP transgene reveals unexpected paternal X-chromosome activity in trophoblastic giant cells of the mouse placenta". Genesis (New York, N.Y. : 2000). 29 (3): 133–40. PMID 11252054.
{{cite journal}}: Check|pmid=value (help) - ^ Wu, H; Luo, J; Yu, H; Rattner, A; Mo, A; Wang, Y; Smallwood, PM; Erlanger, B; Wheelan, SJ; Nathans, J (8 January 2014). "Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease". Neuron. 81 (1): 103–19. doi:10.1016/j.neuron.2013.10.051. PMID 24411735.
- ^ Gimelbrant, A; Hutchinson, JN; Thompson, BR; Chess, A (16 November 2007). "Widespread monoallelic expression on human autosomes". Science (New York, N.Y.). 318 (5853): 1136–40. doi:10.1126/science.1148910. PMID 18006746.
- ^ Jeffries, AR; Perfect, LW; Ledderose, J; Schalkwyk, LC; Bray, NJ; Mill, J; Price, J (September 2012). "Stochastic choice of allelic expression in human neural stem cells". Stem cells (Dayton, Ohio). 30 (9): 1938–47. doi:10.1002/stem.1155. PMID 22714879.
- ^ Li, SM; Valo, Z; Wang, J; Gao, H; Bowers, CW; Singer-Sam, J (2012). "Transcriptome-wide survey of mouse CNS-derived cells reveals monoallelic expression within novel gene families". PloS one. 7 (2): e31751. doi:10.1371/journal.pone.0031751. PMID 22384067.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zwemer, LM; Zak, A; Thompson, BR; Kirby, A; Daly, MJ; Chess, A; Gimelbrant, AA (20 February 2012). "Autosomal monoallelic expression in the mouse". Genome biology. 13 (2): R10. doi:10.1186/gb-2012-13-2-r10. PMID 22348269.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Deng, Q; Ramsköld, D; Reinius, B; Sandberg, R (10 January 2014). "Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells". Science (New York, N.Y.). 343 (6167): 193–6. doi:10.1126/science.1245316. PMID 24408435.
- ^ Pernis, B; Chiappino, G; Kelus, AS; Gell, PG (1 November 1965). "Cellular localization of immunoglobulins with different allotypic specificities in rabbit lymphoid tissues". The Journal of experimental medicine. 122 (5): 853–76. PMID 4159057.
- ^ Hozumi, N; Tonegawa, S (October 1976). "Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions". Proceedings of the National Academy of Sciences of the United States of America. 73 (10): 3628–32. PMID 824647.
- ^ Brady, BL; Steinel, NC; Bassing, CH (1 October 2010). "Antigen receptor allelic exclusion: an update and reappraisal". Journal of immunology (Baltimore, Md. : 1950). 185 (7): 3801–8. doi:10.4049/jimmunol.1001158. PMID 20858891.
- ^ Chess, A; Simon, I; Cedar, H; Axel, R (9 September 1994). "Allelic inactivation regulates olfactory receptor gene expression". Cell. 78 (5): 823–34. PMID 8087849.
- ^ Tanamachi, DM; Hanke, T; Takizawa, H; Jamieson, AM; Raulet, DR (5 February 2001). "Expression of natural killer receptor alleles at different Ly49 loci occurs independently and is regulated by major histocompatibility complex class I molecules". The Journal of experimental medicine. 193 (3): 307–15. PMID 11157051.
- ^ Guo, L; Hu-Li, J; Paul, WE (July 2005). "Probabilistic regulation in TH2 cells accounts for monoallelic expression of IL-4 and IL-13". Immunity. 23 (1): 89–99. doi:10.1016/j.immuni.2005.05.008. PMID 16039582.