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Transcriptional amplification

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Transcriptional amplification involves increases in global levels of mRNAs produced from expressed genes and may be either uniform across all expressed genes or variable from gene to gene.

In genetics, transcriptional amplification is the process in which the total amount of messenger RNA (mRNA) molecules from expressed genes is increased during disease, development, or in response to stimuli.

In eukaryotic cells, the transcribing activity of RNA Polymerase II results in mRNA production. Transcriptional amplification is specifically defined as the increase in per-cell abundance of this set of expressed mRNAs. Transcriptional amplification is caused by changes in the amount or activity of transcription-regulating proteins.

Mechanisms of transcriptional amplification

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Gene expression is regulated by numerous types of proteins that directly or indirectly influence transcription by RNA Polymerase II. As opposed to transcriptional activators or repressors that selectively activate or repress specific genes, amplifiers of transcription act globally on expressed genes.

Several known regulators of transcriptional amplification have been characterized including the oncogene Myc,[1][2] the Rett syndrome protein MECP2,[3] and the BET bromodomain protein BRD4.[4] In particular, the Myc protein amplifies transcription by binding to promoters and enhancers of active genes where it directly recruits the transcription elongation factor P-TEFb. Furthermore, the BRD4 protein is a regulator of Myc activity.

Identifying and measuring transcriptional amplification

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Commonly used gene expression experiments interrogate the expression of one gene (qPCR) or many genes (microarray, RNA-Seq). These techniques generally measure relative mRNA levels and employ normalization methods that assume only a small number of genes show altered expression.[5] In contrast, single cell or cell-count normalized absolute measurements of mRNA abundance are required to reveal transcriptional amplification.[6] Additionally, global measurements of mRNA or total mRNA per cell can also uncover evidence for transcriptional amplification.[7][8]

Cells in which transcription has been amplified have additional hallmarks suggesting that amplification has occurred. Cells with increased mRNA levels may be larger, consistent with an increased abundance of gene products. This increase in the amount of gene products may result in a decreased doubling time.

Role in disease

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Transcriptional amplification has been implicated in cancer,[9][10] Rett syndrome,[11] heart disease,[12] Down syndrome,[13] and cellular aging.[14] In cancer, Myc-driven transcriptional amplification is posited to help tumor cells overcome rate-limiting constraints in growth and proliferation.[15] Drugs that target the transcription or mRNA processing machinery are known to be particularly effective against Myc-driven tumor models,[16][17] suggesting that dampening of transcriptional amplification can have anti-tumor effects. Similarly, small molecules targeting the BET bromodomain protein BRD4, which is up-regulated during heart failure, can block cardiac hypertrophy in mouse models.[18][19] In Rett syndrome, which is caused by loss of function of the transcriptional regulator MeCP2, MeCP2 was shown to specifically amplify transcription in neurons and not neuronal precursors.[20] Restoration of MeCP2 reverses disease symptoms associated with Rett syndrome[21][22]

References

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  1. ^ Lin, CY; Lovén, J; Rahl, PB; Paranal, RM; Burge, CB; Bradner, JE; Lee, TI; Young, RA (28 September 2012). "Transcriptional amplification in tumor cells with elevated c-Myc". Cell. 151 (1): 56–67. doi:10.1016/j.cell.2012.08.026. PMC 3462372. PMID 23021215.
  2. ^ Nie, Z; Hu, G; Wei, G; Cui, K; Yamane, A; Resch, W; Wang, R; Green, DR; Tessarollo, L; Casellas, R; Zhao, K; Levens, D (28 September 2012). "c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells". Cell. 151 (1): 68–79. doi:10.1016/j.cell.2012.08.033. PMC 3471363. PMID 23021216.
  3. ^ Li, Y; Wang, H; Muffat, J; Cheng, AW; Orlando, DA; Lovén, J; Kwok, SM; Feldman, DA; Bateup, HS; Gao, Q; Hockemeyer, D; Mitalipova, M; Lewis, CA; Vander Heiden, MG; Sur, M; Young, RA; Jaenisch, R (3 October 2013). "Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons". Cell Stem Cell. 13 (4): 446–58. doi:10.1016/j.stem.2013.09.001. PMC 4053296. PMID 24094325.
  4. ^ Anand, P; Brown, JD; Lin, CY; Qi, J; Zhang, R; Artero, PC; Alaiti, MA; Bullard, J; Alazem, K; Margulies, KB; Cappola, TP; Lemieux, M; Plutzky, J; Bradner, JE; Haldar, SM (1 August 2013). "BET bromodomains mediate transcriptional pause release in heart failure". Cell. 154 (3): 569–82. doi:10.1016/j.cell.2013.07.013. PMC 4090947. PMID 23911322.
  5. ^ Hannah, MA; Redestig, H; Leisse, A; Willmitzer, L (July 2008). "Global mRNA changes in microarray experiments". Nature Biotechnology. 26 (7): 741–2. doi:10.1038/nbt0708-741. PMID 18612292. S2CID 32566304.
  6. ^ Lovén, J; Orlando, DA; Sigova, AA; Lin, CY; Rahl, PB; Burge, CB; Levens, DL; Lee, TI; Young, RA (26 October 2012). "Revisiting global gene expression analysis". Cell. 151 (3): 476–82. doi:10.1016/j.cell.2012.10.012. PMC 3505597. PMID 23101621.
  7. ^ Lin, CY; Lovén, J; Rahl, PB; Paranal, RM; Burge, CB; Bradner, JE; Lee, TI; Young, RA (28 September 2012). "Transcriptional amplification in tumor cells with elevated c-Myc". Cell. 151 (1): 56–67. doi:10.1016/j.cell.2012.08.026. PMC 3462372. PMID 23021215.
  8. ^ Kanno, J; Aisaki, K; Igarashi, K; Nakatsu, N; Ono, A; Kodama, Y; Nagao, T (29 March 2006). ""Per cell" normalization method for mRNA measurement by quantitative PCR and microarrays". BMC Genomics. 7: 64. doi:10.1186/1471-2164-7-64. PMC 1448209. PMID 16571132.
  9. ^ Lin, CY; Lovén, J; Rahl, PB; Paranal, RM; Burge, CB; Bradner, JE; Lee, TI; Young, RA (28 September 2012). "Transcriptional amplification in tumor cells with elevated c-Myc". Cell. 151 (1): 56–67. doi:10.1016/j.cell.2012.08.026. PMC 3462372. PMID 23021215.
  10. ^ Nie, Z; Hu, G; Wei, G; Cui, K; Yamane, A; Resch, W; Wang, R; Green, DR; Tessarollo, L; Casellas, R; Zhao, K; Levens, D (28 September 2012). "c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells". Cell. 151 (1): 68–79. doi:10.1016/j.cell.2012.08.033. PMC 3471363. PMID 23021216.
  11. ^ Li, Y; Wang, H; Muffat, J; Cheng, AW; Orlando, DA; Lovén, J; Kwok, SM; Feldman, DA; Bateup, HS; Gao, Q; Hockemeyer, D; Mitalipova, M; Lewis, CA; Vander Heiden, MG; Sur, M; Young, RA; Jaenisch, R (3 October 2013). "Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons". Cell Stem Cell. 13 (4): 446–58. doi:10.1016/j.stem.2013.09.001. PMC 4053296. PMID 24094325.
  12. ^ Anand, P; Brown, JD; Lin, CY; Qi, J; Zhang, R; Artero, PC; Alaiti, MA; Bullard, J; Alazem, K; Margulies, KB; Cappola, TP; Lemieux, M; Plutzky, J; Bradner, JE; Haldar, SM (1 August 2013). "BET bromodomains mediate transcriptional pause release in heart failure". Cell. 154 (3): 569–82. doi:10.1016/j.cell.2013.07.013. PMC 4090947. PMID 23911322.
  13. ^ Lane, AA; Chapuy, B; Lin, CY; Tivey, T; Li, H; Townsend, EC; van Bodegom, D; Day, TA; Wu, SC; Liu, H; Yoda, A; Alexe, G; Schinzel, AC; Sullivan, TJ; Malinge, S; Taylor, JE; Stegmaier, K; Jaffe, JD; Bustin, M; te Kronnie, G; Izraeli, S; Harris, MH; Stevenson, KE; Neuberg, D; Silverman, LB; Sallan, SE; Bradner, JE; Hahn, WC; Crispino, JD; Pellman, D; Weinstock, DM (June 2014). "Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation". Nature Genetics. 46 (6): 618–23. doi:10.1038/ng.2949. PMC 4040006. PMID 24747640.
  14. ^ Hu, Z; Chen, K; Xia, Z; Chavez, M; Pal, S; Seol, JH; Chen, CC; Li, W; Tyler, JK (15 February 2014). "Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging". Genes & Development. 28 (4): 396–408. doi:10.1101/gad.233221.113. PMC 3937517. PMID 24532716.
  15. ^ Ruggero, D (1 December 2009). "The role of Myc-induced protein synthesis in cancer". Cancer Research. 69 (23): 8839–43. doi:10.1158/0008-5472.CAN-09-1970. PMC 2880919. PMID 19934336.
  16. ^ Christensen, CL; Kwiatkowski, N; Abraham, BJ; Carretero, J; Al-Shahrour, F; Zhang, T; Chipumuro, E; Herter-Sprie, GS; Akbay, EA; Altabef, A; Zhang, J; Shimamura, T; Capelletti, M; Reibel, JB; Cavanaugh, JD; Gao, P; Liu, Y; Michaelsen, SR; Poulsen, HS; Aref, AR; Barbie, DA; Bradner, JE; George, RE; Gray, NS; Young, RA; Wong, KK (8 December 2014). "Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor". Cancer Cell. 26 (6): 909–22. doi:10.1016/j.ccell.2014.10.019. PMC 4261156. PMID 25490451.
  17. ^ Hsu, TY; Simon, LM; Neill, NJ; Marcotte, R; Sayad, A; Bland, CS; Echeverria, GV; Sun, T; Kurley, SJ; Tyagi, S; Karlin, KL; Dominguez-Vidaña, R; Hartman, JD; Renwick, A; Scorsone, K; Bernardi, RJ; Skinner, SO; Jain, A; Orellana, M; Lagisetti, C; Golding, I; Jung, SY; Neilson, JR; Zhang, XH; Cooper, TA; Webb, TR; Neel, BG; Shaw, CA; Westbrook, TF (17 September 2015). "The spliceosome is a therapeutic vulnerability in MYC-driven cancer". Nature. 525 (7569): 384–8. Bibcode:2015Natur.525..384H. doi:10.1038/nature14985. PMC 4831063. PMID 26331541.
  18. ^ Anand, P; Brown, JD; Lin, CY; Qi, J; Zhang, R; Artero, PC; Alaiti, MA; Bullard, J; Alazem, K; Margulies, KB; Cappola, TP; Lemieux, M; Plutzky, J; Bradner, JE; Haldar, SM (1 August 2013). "BET bromodomains mediate transcriptional pause release in heart failure". Cell. 154 (3): 569–82. doi:10.1016/j.cell.2013.07.013. PMC 4090947. PMID 23911322.
  19. ^ Stratton, MS; Lin, CY; Anand, P; Tatman, PD; Ferguson, BS; Wickers, ST; Ambardekar, AV; Sucharov, CC; Bradner, JE; Haldar, SM; McKinsey, TA (2 August 2016). "Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA". Cell Reports. 16 (5): 1366–78. doi:10.1016/j.celrep.2016.06.074. PMC 4972677. PMID 27425608.
  20. ^ Li, Y; Wang, H; Muffat, J; Cheng, AW; Orlando, DA; Lovén, J; Kwok, SM; Feldman, DA; Bateup, HS; Gao, Q; Hockemeyer, D; Mitalipova, M; Lewis, CA; Vander Heiden, MG; Sur, M; Young, RA; Jaenisch, R (3 October 2013). "Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons". Cell Stem Cell. 13 (4): 446–58. doi:10.1016/j.stem.2013.09.001. PMC 4053296. PMID 24094325.
  21. ^ Luikenhuis, S; Giacometti, E; Beard, CF; Jaenisch, R (20 April 2004). "Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice". Proceedings of the National Academy of Sciences of the United States of America. 101 (16): 6033–8. Bibcode:2004PNAS..101.6033L. doi:10.1073/pnas.0401626101. PMC 395918. PMID 15069197.
  22. ^ Garg, SK; Lioy, DT; Cheval, H; McGann, JC; Bissonnette, JM; Murtha, MJ; Foust, KD; Kaspar, BK; Bird, A; Mandel, G (21 August 2013). "Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome". The Journal of Neuroscience. 33 (34): 13612–20. doi:10.1523/JNEUROSCI.1854-13.2013. PMC 3755711. PMID 23966684.
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