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[[File:Types of transcriptional amplification.svg|frame|right|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, [[Developmental biology|development]], or in response to stimuli.

In eukaryotic cells, the [[Transcription (biology)|transcribing]] activity of [[RNA polymerase II|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==

Gene expression is [[Regulation of gene expression|regulated]] by numerous types of proteins that directly or indirectly influence transcription by RNA Polymerase II. As opposed to transcriptional [[Activator (genetics)|activators]] or [[repressor]]s 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]],<ref>{{cite journal|last1=Lin|first1=CY|last2=Lovén|first2=J|last3=Rahl|first3=PB|last4=Paranal|first4=RM|last5=Burge|first5=CB|last6=Bradner|first6=JE|last7=Lee|first7=TI|last8=Young|first8=RA|title=Transcriptional amplification in tumor cells with elevated c-Myc.|journal=Cell|date=28 September 2012|volume=151|issue=1|pages=56–67|pmid=23021215|pmc=3462372|doi=10.1016/j.cell.2012.08.026}}</ref><ref>{{cite journal|last1=Nie|first1=Z|last2=Hu|first2=G|last3=Wei|first3=G|last4=Cui|first4=K|last5=Yamane|first5=A|last6=Resch|first6=W|last7=Wang|first7=R|last8=Green|first8=DR|last9=Tessarollo|first9=L|last10=Casellas|first10=R|last11=Zhao|first11=K|last12=Levens|first12=D|title=c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.|journal=Cell|date=28 September 2012|volume=151|issue=1|pages=68–79|pmid=23021216|pmc=3471363|doi=10.1016/j.cell.2012.08.033}}</ref> the [[Rett syndrome]] protein [[MECP2]],<ref>{{cite journal|last1=Li|first1=Y|last2=Wang|first2=H|last3=Muffat|first3=J|last4=Cheng|first4=AW|last5=Orlando|first5=DA|last6=Lovén|first6=J|last7=Kwok|first7=SM|last8=Feldman|first8=DA|last9=Bateup|first9=HS|last10=Gao|first10=Q|last11=Hockemeyer|first11=D|last12=Mitalipova|first12=M|last13=Lewis|first13=CA|last14=Vander Heiden|first14=MG|last15=Sur|first15=M|last16=Young|first16=RA|last17=Jaenisch|first17=R|title=Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.|journal=Cell Stem Cell|date=3 October 2013|volume=13|issue=4|pages=446–58|pmid=24094325|pmc=4053296|doi=10.1016/j.stem.2013.09.001}}</ref> and the BET [[bromodomain]] protein [[BRD4]].<ref>{{cite journal|last1=Anand|first1=P|last2=Brown|first2=JD|last3=Lin|first3=CY|last4=Qi|first4=J|last5=Zhang|first5=R|last6=Artero|first6=PC|last7=Alaiti|first7=MA|last8=Bullard|first8=J|last9=Alazem|first9=K|last10=Margulies|first10=KB|last11=Cappola|first11=TP|last12=Lemieux|first12=M|last13=Plutzky|first13=J|last14=Bradner|first14=JE|last15=Haldar|first15=SM|title=BET bromodomains mediate transcriptional pause release in heart failure.|journal=Cell|date=1 August 2013|volume=154|issue=3|pages=569–82|pmid=23911322|pmc=4090947|doi=10.1016/j.cell.2013.07.013}}</ref> In particular, the Myc protein amplifies transcription by binding to [[Promoter (genetics)|promoters]] and [[Enhancer (genetics)|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==

Commonly used gene expression experiments interrogate the expression of one gene ([[Real-time polymerase chain reaction|qPCR]]) or many genes ([[DNA microarray|microarray]], [[RNA-Seq]]). These techniques generally measure relative mRNA levels and employ [[Microarray analysis techniques|normalization methods]] that assume only a small number of genes show altered expression.<ref>{{cite journal|last1=Hannah|first1=MA|last2=Redestig|first2=H|last3=Leisse|first3=A|last4=Willmitzer|first4=L|title=Global mRNA changes in microarray experiments.|journal=Nature Biotechnology|date=July 2008|volume=26|issue=7|pages=741–2|pmid=18612292|doi=10.1038/nbt0708-741|s2cid=32566304}}</ref> In contrast, single cell or cell-count normalized absolute measurements of mRNA abundance are required to reveal transcriptional amplification.<ref>{{cite journal|last1=Lovén|first1=J|last2=Orlando|first2=DA|last3=Sigova|first3=AA|last4=Lin|first4=CY|last5=Rahl|first5=PB|last6=Burge|first6=CB|last7=Levens|first7=DL|last8=Lee|first8=TI|last9=Young|first9=RA|title=Revisiting global gene expression analysis.|journal=Cell|date=26 October 2012|volume=151|issue=3|pages=476–82|pmid=23101621|pmc=3505597|doi=10.1016/j.cell.2012.10.012}}</ref> Additionally, global measurements of mRNA or total mRNA per cell can also uncover evidence for transcriptional amplification.<ref>{{cite journal|last1=Lin|first1=CY|last2=Lovén|first2=J|last3=Rahl|first3=PB|last4=Paranal|first4=RM|last5=Burge|first5=CB|last6=Bradner|first6=JE|last7=Lee|first7=TI|last8=Young|first8=RA|title=Transcriptional amplification in tumor cells with elevated c-Myc.|journal=Cell|date=28 September 2012|volume=151|issue=1|pages=56–67|pmid=23021215|pmc=3462372|doi=10.1016/j.cell.2012.08.026}}</ref><ref>{{cite journal|last1=Kanno|first1=J|last2=Aisaki|first2=K|last3=Igarashi|first3=K|last4=Nakatsu|first4=N|last5=Ono|first5=A|last6=Kodama|first6=Y|last7=Nagao|first7=T|title="Per cell" normalization method for mRNA measurement by quantitative PCR and microarrays.|journal=BMC Genomics|date=29 March 2006|volume=7|pages=64|pmid=16571132|pmc=1448209|doi=10.1186/1471-2164-7-64|doi-access=free}}</ref>

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==

Transcriptional amplification has been implicated in cancer,<ref>{{cite journal|last1=Lin|first1=CY|last2=Lovén|first2=J|last3=Rahl|first3=PB|last4=Paranal|first4=RM|last5=Burge|first5=CB|last6=Bradner|first6=JE|last7=Lee|first7=TI|last8=Young|first8=RA|title=Transcriptional amplification in tumor cells with elevated c-Myc.|journal=Cell|date=28 September 2012|volume=151|issue=1|pages=56–67|pmid=23021215|pmc=3462372|doi=10.1016/j.cell.2012.08.026}}</ref><ref>{{cite journal|last1=Nie|first1=Z|last2=Hu|first2=G|last3=Wei|first3=G|last4=Cui|first4=K|last5=Yamane|first5=A|last6=Resch|first6=W|last7=Wang|first7=R|last8=Green|first8=DR|last9=Tessarollo|first9=L|last10=Casellas|first10=R|last11=Zhao|first11=K|last12=Levens|first12=D|title=c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.|journal=Cell|date=28 September 2012|volume=151|issue=1|pages=68–79|pmid=23021216|pmc=3471363|doi=10.1016/j.cell.2012.08.033}}</ref> Rett syndrome,<ref>{{cite journal|last1=Li|first1=Y|last2=Wang|first2=H|last3=Muffat|first3=J|last4=Cheng|first4=AW|last5=Orlando|first5=DA|last6=Lovén|first6=J|last7=Kwok|first7=SM|last8=Feldman|first8=DA|last9=Bateup|first9=HS|last10=Gao|first10=Q|last11=Hockemeyer|first11=D|last12=Mitalipova|first12=M|last13=Lewis|first13=CA|last14=Vander Heiden|first14=MG|last15=Sur|first15=M|last16=Young|first16=RA|last17=Jaenisch|first17=R|title=Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.|journal=Cell Stem Cell|date=3 October 2013|volume=13|issue=4|pages=446–58|pmid=24094325|pmc=4053296|doi=10.1016/j.stem.2013.09.001}}</ref> heart disease,<ref>{{cite journal|last1=Anand|first1=P|last2=Brown|first2=JD|last3=Lin|first3=CY|last4=Qi|first4=J|last5=Zhang|first5=R|last6=Artero|first6=PC|last7=Alaiti|first7=MA|last8=Bullard|first8=J|last9=Alazem|first9=K|last10=Margulies|first10=KB|last11=Cappola|first11=TP|last12=Lemieux|first12=M|last13=Plutzky|first13=J|last14=Bradner|first14=JE|last15=Haldar|first15=SM|title=BET bromodomains mediate transcriptional pause release in heart failure.|journal=Cell|date=1 August 2013|volume=154|issue=3|pages=569–82|pmid=23911322|pmc=4090947|doi=10.1016/j.cell.2013.07.013}}</ref> [[Down syndrome]],<ref>{{cite journal|last1=Lane|first1=AA|last2=Chapuy|first2=B|last3=Lin|first3=CY|last4=Tivey|first4=T|last5=Li|first5=H|last6=Townsend|first6=EC|last7=van Bodegom|first7=D|last8=Day|first8=TA|last9=Wu|first9=SC|last10=Liu|first10=H|last11=Yoda|first11=A|last12=Alexe|first12=G|last13=Schinzel|first13=AC|last14=Sullivan|first14=TJ|last15=Malinge|first15=S|last16=Taylor|first16=JE|last17=Stegmaier|first17=K|last18=Jaffe|first18=JD|last19=Bustin|first19=M|last20=te Kronnie|first20=G|last21=Izraeli|first21=S|last22=Harris|first22=MH|last23=Stevenson|first23=KE|last24=Neuberg|first24=D|last25=Silverman|first25=LB|last26=Sallan|first26=SE|last27=Bradner|first27=JE|last28=Hahn|first28=WC|last29=Crispino|first29=JD|last30=Pellman|first30=D|last31=Weinstock|first31=DM|title=Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation.|journal=Nature Genetics|date=June 2014|volume=46|issue=6|pages=618–23|pmid=24747640|pmc=4040006|doi=10.1038/ng.2949}}</ref> and cellular aging.<ref>{{cite journal|last1=Hu|first1=Z|last2=Chen|first2=K|last3=Xia|first3=Z|last4=Chavez|first4=M|last5=Pal|first5=S|last6=Seol|first6=JH|last7=Chen|first7=CC|last8=Li|first8=W|last9=Tyler|first9=JK|title=Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.|journal=Genes & Development|date=15 February 2014|volume=28|issue=4|pages=396–408|pmid=24532716|pmc=3937517|doi=10.1101/gad.233221.113}}</ref> In cancer, Myc-driven transcriptional amplification is posited to help tumor cells overcome rate-limiting constraints in growth and proliferation.<ref>{{cite journal|last1=Ruggero|first1=D|title=The role of Myc-induced protein synthesis in cancer.|journal=Cancer Research|date=1 December 2009|volume=69|issue=23|pages=8839–43|pmid=19934336|pmc=2880919|doi=10.1158/0008-5472.CAN-09-1970}}</ref> Drugs that target the transcription or mRNA processing machinery are known to be particularly effective against Myc-driven tumor models,<ref>{{cite journal|last1=Christensen|first1=CL|last2=Kwiatkowski|first2=N|last3=Abraham|first3=BJ|last4=Carretero|first4=J|last5=Al-Shahrour|first5=F|last6=Zhang|first6=T|last7=Chipumuro|first7=E|last8=Herter-Sprie|first8=GS|last9=Akbay|first9=EA|last10=Altabef|first10=A|last11=Zhang|first11=J|last12=Shimamura|first12=T|last13=Capelletti|first13=M|last14=Reibel|first14=JB|last15=Cavanaugh|first15=JD|last16=Gao|first16=P|last17=Liu|first17=Y|last18=Michaelsen|first18=SR|last19=Poulsen|first19=HS|last20=Aref|first20=AR|last21=Barbie|first21=DA|last22=Bradner|first22=JE|last23=George|first23=RE|last24=Gray|first24=NS|last25=Young|first25=RA|last26=Wong|first26=KK|title=Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.|journal=Cancer Cell|date=8 December 2014|volume=26|issue=6|pages=909–22|pmid=25490451|pmc=4261156|doi=10.1016/j.ccell.2014.10.019}}</ref><ref>{{cite journal|last1=Hsu|first1=TY|last2=Simon|first2=LM|last3=Neill|first3=NJ|last4=Marcotte|first4=R|last5=Sayad|first5=A|last6=Bland|first6=CS|last7=Echeverria|first7=GV|last8=Sun|first8=T|last9=Kurley|first9=SJ|last10=Tyagi|first10=S|last11=Karlin|first11=KL|last12=Dominguez-Vidaña|first12=R|last13=Hartman|first13=JD|last14=Renwick|first14=A|last15=Scorsone|first15=K|last16=Bernardi|first16=RJ|last17=Skinner|first17=SO|last18=Jain|first18=A|last19=Orellana|first19=M|last20=Lagisetti|first20=C|last21=Golding|first21=I|last22=Jung|first22=SY|last23=Neilson|first23=JR|last24=Zhang|first24=XH|last25=Cooper|first25=TA|last26=Webb|first26=TR|last27=Neel|first27=BG|last28=Shaw|first28=CA|last29=Westbrook|first29=TF|title=The spliceosome is a therapeutic vulnerability in MYC-driven cancer.|journal=Nature|date=17 September 2015|volume=525|issue=7569|pages=384–8|pmid=26331541|pmc=4831063|doi=10.1038/nature14985|bibcode=2015Natur.525..384H }}</ref> 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.<ref>{{cite journal|last1=Anand|first1=P|last2=Brown|first2=JD|last3=Lin|first3=CY|last4=Qi|first4=J|last5=Zhang|first5=R|last6=Artero|first6=PC|last7=Alaiti|first7=MA|last8=Bullard|first8=J|last9=Alazem|first9=K|last10=Margulies|first10=KB|last11=Cappola|first11=TP|last12=Lemieux|first12=M|last13=Plutzky|first13=J|last14=Bradner|first14=JE|last15=Haldar|first15=SM|title=BET bromodomains mediate transcriptional pause release in heart failure.|journal=Cell|date=1 August 2013|volume=154|issue=3|pages=569–82|pmid=23911322|pmc=4090947|doi=10.1016/j.cell.2013.07.013}}</ref><ref>{{cite journal|last1=Stratton|first1=MS|last2=Lin|first2=CY|last3=Anand|first3=P|last4=Tatman|first4=PD|last5=Ferguson|first5=BS|last6=Wickers|first6=ST|last7=Ambardekar|first7=AV|last8=Sucharov|first8=CC|last9=Bradner|first9=JE|last10=Haldar|first10=SM|last11=McKinsey|first11=TA|title=Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.|journal=Cell Reports|date=2 August 2016|volume=16|issue=5|pages=1366–78|pmid=27425608|pmc=4972677|doi=10.1016/j.celrep.2016.06.074}}</ref> 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.<ref>{{cite journal|last1=Li|first1=Y|last2=Wang|first2=H|last3=Muffat|first3=J|last4=Cheng|first4=AW|last5=Orlando|first5=DA|last6=Lovén|first6=J|last7=Kwok|first7=SM|last8=Feldman|first8=DA|last9=Bateup|first9=HS|last10=Gao|first10=Q|last11=Hockemeyer|first11=D|last12=Mitalipova|first12=M|last13=Lewis|first13=CA|last14=Vander Heiden|first14=MG|last15=Sur|first15=M|last16=Young|first16=RA|last17=Jaenisch|first17=R|title=Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.|journal=Cell Stem Cell|date=3 October 2013|volume=13|issue=4|pages=446–58|pmid=24094325|pmc=4053296|doi=10.1016/j.stem.2013.09.001}}</ref> Restoration of MeCP2 reverses disease symptoms associated with Rett syndrome<ref>{{cite journal|last1=Luikenhuis|first1=S|last2=Giacometti|first2=E|last3=Beard|first3=CF|last4=Jaenisch|first4=R|title=Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=20 April 2004|volume=101|issue=16|pages=6033–8|pmid=15069197|pmc=395918|doi=10.1073/pnas.0401626101|bibcode=2004PNAS..101.6033L|doi-access=free}}</ref><ref>{{cite journal|last1=Garg|first1=SK|last2=Lioy|first2=DT|last3=Cheval|first3=H|last4=McGann|first4=JC|last5=Bissonnette|first5=JM|last6=Murtha|first6=MJ|last7=Foust|first7=KD|last8=Kaspar|first8=BK|last9=Bird|first9=A|last10=Mandel|first10=G|title=Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome.|journal=The Journal of Neuroscience |date=21 August 2013|volume=33|issue=34|pages=13612–20|pmid=23966684|pmc=3755711|doi=10.1523/JNEUROSCI.1854-13.2013}}</ref>

== References ==

{{reflist}}

[[Category:Genetics]]

Transcriptional amplification - История изменений

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