Implications of the gene balance hypothesis for dosage compensation

Abstract

Dosage compensation refers to the equal expression between the sexes despite the fact that the dosage of the X chromosome is different in males and females. In BoldItalic there is a twofold upregulation of the single male X. In triple X metafemales, there is also dosage compensation, which occurs by a two-thirds downregulation. There is a concomitant reduction in expression of many autosomal genes in metafemales. The male specific lethal (MSL) complex is present on the male X chromosome. Evidence is discussed showing that the MSL complex sequesters a histone acetyltransferase to the X chromosome to mute an otherwise increased expression by diminishing the histone acetylation on the autosomes. Several lines of evidence indicate that a constraining activity occurs from the MSL complex to prevent overcompensation on the X that might otherwise occur from the high level of acetylation present. Together, the evidence suggests that dosage compensation is a modification of a regulatory inverse dosage effect that is a reflection of intrinsic gene regulatory mechanisms and that the MSL complex has evolved in reaction in order to equalize the expression on both the X and autosomes of males and females.

Keywords

inverse dosage effect / male specific lethal complex / histone acetylation / metafemales

References

[1] Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar J M, Potier M C (2007). Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet, 81(3): 475–491

[2] Akhtar A, Becker P B (2000). Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol Cell, 5(2): 367–375

[3] Altug-Teber O, Bonin M, Walter M, Mau-Holzmann U A, Dufke A, Stappert H, Tekesin I, Heilbronner H, Nieselt K, Riess O (2007). Specific transcriptional changes in human fetuses with autosomal trisomies. Cytogenet Genome Res, 119(3-4): 171–184

[4] Arkhipova I R, Li J, Meselson M (1997). On the mode of gene-dosage compensation in Drosophila. Genetics, 145(3): 729–736

[5] Badenhorst P, Voas M, Rebay I, Wu C (2002). Biological functions of the ISWI chromatin remodeling complex NURF. Genes Dev, 16(24): 3186–3198

[6] Bahn S, Mimmack M, Ryan M, Caldwell M A, Jauniaux E, Starkey M, Svendsen C N, Emson P (2002). Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study. Lancet, 359(9303): 310–315

[7] Belote J M, Lucchesi J C (1980). Control of X chromosome transcription by the maleless gene in Drosophila. Nature, 285(5766): 573–575

[8] Bhadra M P, Bhadra U, Kundu J, Birchler J A (2005). Gene expression analysis of the function of the male-specific lethal complex in Drosophila. Genetics, 169(4): 2061–2074

[9] Bhadra U, Pal-Bhadra M, Birchler J A (1999). Role of the male specific lethal (msl) genes in modifying the effects of sex chromosomal dosage in Drosophila. Genetics, 152(1): 249–268

[10] Bhadra U, Pal-Bhadra M, Birchler J A (2000). Histone acetylation and gene expression analysis of sex lethal mutants in Drosophila. Genetics, 155(2): 753–763

[11] Birchler J A (1979). A study of enzyme activities in a dosage series of the long arm of chromosome one in maize. Genetics, 92(4): 1211–1229

[12] Birchler J A (1981). The genetic basis of dosage compensation of alcohol dehydrogenase-1 in maize. Genetics, 97(3-4): 625–637

[13] Birchler J A (1984). Genetic analysis of a modifier of the sexual dimorphism of glass in Drosophila melanogaster. Genet Res, 44(02): 125–132

[14] Birchler J A (1992). Expression of cis-regulatory mutations of the white locus in metafemales of Drosophila melanogaster. Genet Res, 59(1): 11–18

[15] Birchler J A (1996). X chromosome dosage compensation in Drosophila. Science, 272(5265): 1190–1191

[16] Birchler J A (2010). Reflections on studies of gene expression in aneuploids. Biochem J, 426(2): 119–123

[17] Birchler J A, Bhadra U, Bhadra M P, Auger D L (2001). Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits. Dev Biol, 234(2): 275–288

[18] Birchler J A, Hiebert J C, Krietzman M (1989). Gene expression in adult metafemales of Drosophila melanogaster. Genetics, 122(4): 869–879

[19] Birchler J A, Hiebert J C, Paigen K (1990). Analysis of autosomal dosage compensation involving the alcohol dehydrogenase locus in Drosophila melanogaster. Genetics, 124(3): 679–686

[20] Birchler J A, Newton K J (1981). Modulation of protein levels in chromosomal dosage series of maize: the biochemical basis of aneuploid syndromes. Genetics, 99(2): 247–266

[21] Birchler J A, Riddle N C, Auger D L, Veitia R A (2005). Dosage balance in gene regulation: biological implications. Trends Genet, 21(4): 219–226

[22] Birchler J A, Veitia R A (2007). The gene balance hypothesis: from classical genetics to modern genomics. Plant Cell, 19(2): 395–402

[23] Birchler J A, Veitia R A (2010). The gene balance hypothesis: implications for gene regulation, quantitative traits and evolution. New Phytol, 186(1): 54–62

[24] Bone J R, Lavender J, Richman R, Palmer M J, Turner B M, Kuroda M I (1994). Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. Genes Dev, 8(1): 96–104

[25] Brehm A, Längst G, Kehle J, Clapier C R, Imhof A, Eberharter A, Müller J, Becker P B (2000). dMi-2 and ISWI chromatin remodelling factors have distinct nucleosome binding and mobilization properties. EMBO J, 19(16): 4332–4341

[26] Corona D F, Clapier C R, Becker P B, Tamkun J W (2002). Modulation of ISWI function by site-specific histone acetylation. EMBO Rep, 3(3): 242–247

[27] Delattre M, Spierer A, Jaquet Y, Spierer P (2004). Increased expression of DrosophilaSu(var)3-7 triggers Su(var)3-9-dependent heterochromatin formation. J Cell Sci, 117(Pt 25): 6239–6247

[28] Deuring R, Fanti L, Armstrong J A, Sarte M, Papoulas O, Prestel M, Daubresse G, Verardo M, Moseley S L, Berloco M, Tsukiyama T, Wu C, Pimpinelli S, Tamkun J W (2000). The ISWI chromatin-remodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Mol Cell, 5(2): 355–365

[29] Devlin R H, Holm D G, Grigliatti T A (1982). Autosomal dosage compensation Drosophila melanogaster strains trisomic for the left arm of chromosome 2. Proc Natl Acad Sci U S A, 79(4): 1200–1204

[30] Devlin R H, Holm D G, Grigliatti T A (1988). The influence of whole-arm trisomy on gene expression in Drosophila. Genetics, 118(1): 87–101

[31] Dreesen T D, Henikoff S, Loughney K (1991). A pairing-sensitive element that mediates trans-inactivation is associated with the Drosophila brown gene. Genes Dev, 5(3): 331–340

[32] Gergen J P (1987). Dosage compensation in Drosophila: Evidence that daughterless and Sex-lethal control X chromosome activity at the blastoderm stage of embryogenesis. Genetics, 117(3): 477–485

[33] Grell E H (1962). The dose effect of ma-l⁺ and ry⁺ on xanthine dehydrogenase activity in Drosophila melanogaster. Z Vererbungsl, 93(3): 371–377

[34] Guo M, Birchler J A (1994). Trans-acting dosage effects on the expression of model gene systems in maize aneuploids. Science, 266(5193): 1999–2002

[35] Gupta V, Parisi M, Sturgill D, Nuttall R, Doctolero M, Dudko O K, Malley J D, Eastman P S, Oliver B (2006). Global analysis of X-chromosome dosage compensation. J Biol, 5(1): 3

[36] Hiebert J C, Birchler J A (1994). Effects of the maleless mutation on X and autosomal gene expression in Drosophila melanogaster. Genetics, 136(3): 913–926

[37] Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi J C (1997). mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J, 16(8): 2054–2060

[38] Jin Y, Wang Y, Johansen J, Johansen K M (2000). JIL-1, a chromosomal kinase implicated in regulation of chromatin structure, associates with the male specific lethal (MSL) dosage compensation complex. J Cell Biol, 149(5): 1005–1010

[39] Jin Y, Wang Y, Walker D L, Dong H, Conley C, Johansen J, Johansen K M (1999). JIL-1: a novel chromosomal tandem kinase implicated in transcriptional regulation in Drosophila. Mol Cell, 4(1): 129–135

[40] Kelley R L, Kuroda M I (1995). Equality for X chromosomes. Science, 270(5242): 1607–1610

[41] Kind J, Vaquerizas J M, Gebhardt P, Gentzel M, Luscombe N M, Bertone P, Akhtar A (2008). Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell, 133(5): 813–828

[42] Kuroda M I, Kernan M J, Kreber R, Ganetzky B, Baker B S (1991). The maleless protein associates with the X chromosome to regulate dosage compensation in Drosophila. Cell, 66(5): 935–947

[43] Lucchesi J C, Belote J M, Maroni G (1977). X-linked gene activity in metamales (XY;3A) of Drosophila. Chromosoma, 65(1): 1–7

[44] Lucchesi J C, Kelly W G, Panning B (2005). Chromatin remodeling in dosage compensation. Annu Rev Genet, 39(1): 615–651

[45] Lucchesi J C, Rawls J M Jr (1973a). Regulation of gene function: a comparison of enzyme activity levels in relation to gene dosage in diploids and triploids of Drosophila melanogaster. Biochem Genet, 9(1): 41–51

[46] Lucchesi J C, Rawls J M Jr, Maroni G (1974). Gene dosage compensation in metafemales (3X;2A) of Drosophila. Nature, 248(449): 564–567

[47] Lucchesi J C, Rawls R M Jr (1973b). Regulation of gene function: a comparison of X-linked enzyme activity levels in normal and intersexual triploids of Drosophila melanogaster. Genetics, 73(3): 459–464

[48] Lyle R, Gehrig C, Neergaard-Henrichsen C, Deutsch S, Antonarakis S E (2004). Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res, 14(7): 1268–1274

[49] Margolis O S (1934). The effect of a supernumerary X chromosome on members of the Bar series of Drosophila. Genetics, 19(1): 18–24

[50] Maroni G, Plaut W (1973). Dosage compensation in Drosophila melanogaster triploids. I. Autoradiographic study. Chromosoma, 40(4): 361–377

[51] Meller V H, Rattner B P (2002). The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex. EMBO J, 21(5): 1084–1091

[52] Meller V H, Wu K H, Roman G, Kuroda M I, Davis R L (1997). roX1 RNA paints the X chromosome of male Drosophila and is regulated by the dosage compensation system. Cell, 88(4): 445–457

[53] Muller H J (1932). Further studies on the nature and causes of gene mutations. Proc 6th Int Congr Genetics, 1: 213–255

[54] Okuno T, Satou T, Oishi K (1984). Studies on the sex-specific lethals of Drosophila melanogaster. VII. Sex-specific lethals that do not affect dosage compensation. Jpn J Genet, 59(3): 237–247

[55] Pal-Bhadra M, Bhadra U, Birchler J A (1997). Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent. Cell, 90(3): 479–490

[56] Pal-Bhadra M, Bhadra U, Birchler J A (1999). Cosuppression of nonhomologous transgenes in Drosophila involves mutually related endogenous sequences. Cell, 99(1): 35–46

[57] Pal Bhadra M, Bhadra U, Birchler J A (2006). Misregulation of Sex-lethal and disruption of MSL localization in Drosophila species hybrids. Genetics, 174: 1151–1159

[58] Parisi M, Nuttall R, Naiman D, Bouffard G, Malley J, Andrews J, Eastman S, Oliver B (2003). Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science, 299(5607): 697–700

[59] Phillips J L, Hayward S W, Wang Y, Vasselli J, Pavlovich C, Padilla-Nash H, Pezullo J R, Ghadimi B M, Grossfeld G D, Rivera A, Linehan W M, Cunha G R, Ried T (2001). The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis. Cancer Res, 61(22): 8143–8149

[60] Prestel M, Feller C, Straub T, Mitlöhner H, Becker P B (2010). The activation potential of MOF is constrained for dosage compensation. Mol Cell, 38(6): 815–826

[61] Qian S, Pirrotta V (1995). Dosage compensation of the Drosophilawhite gene requires both the X chromosome environment and multiple intragenic elements. Genetics, 139(2): 733–744

[62] Rabinow L, Nguyen-Huynh A T, Birchler J A (1991). A trans-acting regulatory gene that inversely affects the expression of the white, brown and scarlet loci in Drosophila. Genetics, 129(2): 463–480

[63] Rastelli L, Kuroda M I (1998). An analysis of maleless and histone H4 acetylation in Drosophila melanogaster spermatogenesis. Mech Dev, 71(1-2): 107–117

[64] Roseman R R, Swan J M, Geyer P K (1995). A Drosophila insulator protein facilitates dosage compensation of the X chromosome min-white gene located at autosomal insertion sites. Development, 121(11): 3573–3582

[65] Ruiz M F, Esteban M R, Doñoro C, Goday C, Sánchez L (2000). Evolution of dosage compensation in Diptera: the gene maleless implements dosage compensation in Drosophila (Brachycera suborder) but its homolog in Sciara (Nematocera suborder) appears to play no role in dosage compensation. Genetics, 156(4): 1853–1865

[66] Sabl J F, Birchler J A (1993). Dosage dependent modifiers of white alleles in Drosophila melanogaster. Genet Res, 62(1): 15–22

[67] Saran N G, Pletcher M T, Natale J E, Cheng Y, Reeves R H (2003). Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum Mol Genet, 12(16): 2013–2019

[68] Smith P D, Lucchesi J C (1969). The role of sexuality in dosage compensation in Drosophila. Genetics, 61(3): 607–618

[69] Spierer A, Seum C, Delattre M, Spierer P (2005). Loss of the modifiers of variegation Su(var)3-7 or HP1 impacts male X polytene chromosome morphology and dosage compensation. J Cell Sci, 118(Pt 21): 5047–5057

[70] Stern C (1960). Dosage compensation–development of a concept and new facts. Can J Genet Cytol, 2: 105–118

[71] Sun X, Birchler J A (2009). Interaction study of the male specific lethal (MSL) complex and trans-acting dosage effects in metafemales of Drosophila melanogaster. Cytogenet Genome Res, 124(3-4): 298–311

[72] Turner B M, Birley A J, Lavender J (1992). Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell, 69(2): 375–384

[73] Veitia R A, Birchler J A (2010). Dominance and gene dosage balance in human health and disease. J Pathol, 220: 174–185

[74] Veitia R A, Bottani S, Birchler J A (2008). Cellular reactions to gene dosage imbalance: genomic, transcriptomic and proteomic effects. Trends Genet, 24(8): 390–397

[75] Wang Y, Zhang W, Jin Y, Johansen J, Johansen K M (2001). The JIL-1 tandem kinase mediates histone H3 phosphorylation and is required for maintenance of chromatin structure in Drosophila. Cell, 105(4): 433–443

[76] Weiler K S, Wakimoto B T (1995). Heterochromatin and gene expression in Drosophila. Annu Rev Genet, 29(1): 577–605

Acknowledgement

Research supported by National Institutes of Health grant RO1GM068042-05.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg