Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation

Expression of human asparagine synthetase (ASNS), which catalyzes asparagine and glutamate biosynthesis, is transcriptionally induced following amino acid deprivation. Previous overexpression and electrophoresis mobility shift analysis showed the involvement of the transcription factors ATF4, C/EBPβ, and ATF3-FL through the nutrient-sensing response element-1 (NSRE-1) within the ASNS promoter. Amino acid deprivation caused an elevated mRNA level for ATF4, C/EBPβ, and ATF3-FL, and the present study established that the nuclear protein content for ATF4 and ATF3-FL were increased during amino acid limitation, whereas C/EBPβ-LIP declined slightly. The total amount of C/EBPβ-LAP protein was unchanged, but changes in the distribution among multiple C/EBPβ-LAP forms were observed. Overexpression studies established that ATF4, ATF3-FL, and C/EBPβ-LAP could coordinately modulate the transcription from the human ASNS promoter. Chromatin immunoprecipitation demonstrated that amino acid deprivation increased ATF3-FL, ATF4, and C/EBPβ binding to the ASNS promoter and enhanced promoter association of RNA polymerase II, TATA-binding protein, and TFIIB of the general transcription machinery. A time course revealed a markedly different temporal order of interaction between these transcription factors and the ASNS promoter. During the initial 2 h, there was a 20-fold increase in ATF4 binding and a rapid increase in histone H3 and H4 acetylation, which closely paralleled the increased transcription rate of the ASNS gene, whereas the increase in ATF3-FL and C/EBPβ binding was considerably slower and more closely correlated with the decline in transcription rate between 2 and 6 h. The data suggest that ATF3-FL and C/EBPβ act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation. Expression of human asparagine synthetase (ASNS), which catalyzes asparagine and glutamate biosynthesis, is transcriptionally induced following amino acid deprivation. Previous overexpression and electrophoresis mobility shift analysis showed the involvement of the transcription factors ATF4, C/EBPβ, and ATF3-FL through the nutrient-sensing response element-1 (NSRE-1) within the ASNS promoter. Amino acid deprivation caused an elevated mRNA level for ATF4, C/EBPβ, and ATF3-FL, and the present study established that the nuclear protein content for ATF4 and ATF3-FL were increased during amino acid limitation, whereas C/EBPβ-LIP declined slightly. The total amount of C/EBPβ-LAP protein was unchanged, but changes in the distribution among multiple C/EBPβ-LAP forms were observed. Overexpression studies established that ATF4, ATF3-FL, and C/EBPβ-LAP could coordinately modulate the transcription from the human ASNS promoter. Chromatin immunoprecipitation demonstrated that amino acid deprivation increased ATF3-FL, ATF4, and C/EBPβ binding to the ASNS promoter and enhanced promoter association of RNA polymerase II, TATA-binding protein, and TFIIB of the general transcription machinery. A time course revealed a markedly different temporal order of interaction between these transcription factors and the ASNS promoter. During the initial 2 h, there was a 20-fold increase in ATF4 binding and a rapid increase in histone H3 and H4 acetylation, which closely paralleled the increased transcription rate of the ASNS gene, whereas the increase in ATF3-FL and C/EBPβ binding was considerably slower and more closely correlated with the decline in transcription rate between 2 and 6 h. The data suggest that ATF3-FL and C/EBPβ act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation. Mammalian cells have evolved complex cellular responses to changes in environment, including nutrient availability. The asparagine synthetase gene, ASNS, encoding the enzyme that catalyzes the synthesis of asparagine and glutamate using glutamine and aspartate, is a gene for which transcription is highly regulated by the nutritional status of the cell (1Kilberg M.S. Barbosa-Tessmann I.P. J. Nutr. 2002; 132: 1801-1804Crossref PubMed Scopus (33) Google Scholar). Promoter analysis of the human ASNS gene by Barbosa-Tessmann et al. (2Barbosa-Tessmann I.P. Chen C. Zhong C. Siu F. Schuster S.M. Nick H.S. Kilberg M.S. J. Biol. Chem. 2000; 275: 26976-26985Abstract Full Text Full Text PDF PubMed Google Scholar) demonstrated the presence of two cis-elements, termed nutrient-sensing response elements (NSRE-1, nt –68 to –60; NSRE-2, nt –48 to –43) in the ASNS promoter region. Both of these elements are essential for transcriptional activation through either the amino acid response (AAR) 1The abbreviations used are: AAR, amino acid response; AARE, amino acid response element; ATF, activating transcription factor; C/EBP, CCAAT/enhancer-binding protein; NSRE, nutrient sensing response element; RT, reverse transcription; qPCR, quantitative real-time PCR; qRT-PCR, quantitative real-time RT-PCR; ChIP, chromatin immunoprecipitation; ER, endoplasmic reticulum; ERSE, ER stress response element; CMV, cytomegalovirus; CHOP, C/EBP homology protein; MEM, minimal essential medium; nt, nucleotide(s); pol II, polymerase II; HAT, histone acetyltransferase; PCAF, p300/CREB-associated factor. pathway following amino acid deprivation or the endoplasmic reticulum stress response pathway, also known as the unfolded protein response, following glucose deprivation or other ER stress conditions. Although the NSRE-2-binding proteins are unknown, transient expression and electrophoresis shift analysis have demonstrated that activation of the ASNS gene involves activating transcription factor 4 (ATF4) (3Siu F. Bain P.J. LeBlanc-Chaffin R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; 277: 24120-24127Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), ATF3 (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar), and CCAAT/enhancer-binding protein β (C/EBPβ) (5Siu F.Y. Chen C. Zhong C. Kilberg M.S. J. Biol. Chem. 2001; 276: 48100-48107Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) action via the NSRE-1 site. ATF and C/EBP proteins are subfamilies of the larger bZIP (basic transcription factor ATF4 is in a of and cell 2001; PubMed Scopus Google Scholar). Both transcription (3Siu F. Bain P.J. LeBlanc-Chaffin R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; 277: 24120-24127Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar) and H. R. 2000; Full Text Full Text PDF PubMed Scopus Google PubMed Scopus Google Scholar) of ATF4 are increased in stress protein synthesis is in the of ATF4 as ASNS, CHOP, and from ATF4 mRNA is enhanced in stress that to including amino acid deprivation J. Biol. 2002; PubMed Scopus Google Scholar), ER stress H. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), the presence of RNA F. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and Chen Biol. 2002; PubMed Scopus Google Scholar). ATF3 is in and cells but induced in response to stress and is to in a of cellular Google C. J. J. 2002; PubMed Scopus (68) Google Scholar). the of activated transcription from the ATF3 gene in different mRNA encoding proteins of different and (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google C. J. J. 2002; PubMed Scopus (68) Google J. J. Biol. Chem. Full Text PDF PubMed Google J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). The protein, as a in which to or as a with other bZIP in which either or transcription 2001; PubMed Scopus Google Scholar). et al. (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) and et al. Biol. PubMed Scopus Google Scholar) demonstrated that the expression of ATF3 is induced in response to amino acid deprivation or to ER by the and et al. (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) also that deprivation to of ATF3 that an mRNA encoding a ATF3 protein is C/EBPβ is a of a transcription factor including and C/EBPβ is in a of cellular as cellular and J. 2002; PubMed Google Scholar). et al. J. PubMed Scopus Google J. PubMed Scopus Google Scholar) that the mRNA content of C/EBPβ is increased by amino acid deprivation. Siu et al. (5Siu F.Y. Chen C. Zhong C. Kilberg M.S. J. Biol. Chem. 2001; 276: 48100-48107Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) showed that is C/EBPβ mRNA increased by deprivation of but there is also increased binding for C/EBPβ in the nuclear The present study was to the expression of ATF4, and C/EBPβ protein following amino acid and to the temporal of ATF4, and C/EBPβ with the ASNS promoter using chromatin immunoprecipitation have that a of histone status within the ASNS promoter the gene is activated following amino acid deprivation. of is correlated with changes in chromatin during are by of H3 H4 within promoter C. C. F. J. PubMed Scopus Google Scholar). a time course of following amino acid revealed a rapid within in ATF4 binding and of H3 and with the association of the general transcription these changes closely paralleled the increase in transcription rate from the ASNS there was increased binding of ATF3-FL and C/EBPβ to the ASNS which between 2 and 4 and was more closely with the decline in transcription The that following amino acid there is a order of association for a of bZIP transcription factors that to the ASNS promoter NSRE-1 and that factor binding is by of following were from ATF4, C/EBPβ, RNA polymerase II, and PCAF, histone for and and histone H4 and were from cells were in minimal essential to amino 4 and were in a that ASNS promoter is induced by nutrient cell were with and for to to that the cells were in the Amino acid deprivation was by the cells for in or RNA and cellular RNA was from cells using the 2 of RNA was and in to a of the amount of ASNS quantitative real-time analysis was using a 2 and with The for and The were for by for to the polymerase and of of for and for were by increase of the from to to that a was in the mRNA level was also the time as the The for and was in with from and the the of the between were by RNA was from cells using the including to the transcription rate from the ASNS gene, from ASNS and were used to for transcription rate is that by and R. PubMed Scopus Google Scholar), that were by reverse were as a to from were The for and The were for by for to the polymerase and of of for and for were by increase of the from to to that a was in the cell or nuclear were the time and was a or a and to a The was with to for and with and for 2 with was using ATF3-FL, ATF4, or C/EBPβ an of in for 2 The were in a and with a for The were for in and 2 in and The was using an enhanced and the to and was by the ASNS promoter of the gene using the of the The expression of the ATF4 by ATF3-FL by The and C/EBPβ-LAP by via of was by the promoter. cells were with a of 6 of to of of the was used with the of the transcription factor expression The total amount of was among by the of following the cells were to for cellular for analysis of the cells were with and with of by The were and of cell was used for using the and the was with a The are to protein content for to were for and were analysis was to a of cells were with and for h. were to to either or for the time in was by to the to a of and by 2 to a of chromatin was by using a for of with between from cells was with 2 of A was used as the The complex was by protein The in the complex were by the for and using a was by and by used for the and reverse ASNS The were by quantitative real-time with and using to the ASNS promoter nt to NSRE-1 and are The analysis was using the 2 and with of chromatin were used to a for the amount of for the and the were using the The were for to the by for and for for were by in the from to to that a was in the The are as the to from were and the of the between were by the of Amino ASNS mRNA and is known that the ASNS mRNA content of cells is increased of amino acid limitation, a of study is to increase is human cells were in for and the mRNA level for ASNS was for by initial increase in ASNS mRNA content was 2 of deprivation and a of the h. Although there was a of decline from to h, the level was elevated by the Although that increased transcription to the increase in ASNS mRNA (2Barbosa-Tessmann I.P. Chen C. Zhong C. Siu F. Schuster S.M. Nick H.S. Kilberg M.S. J. Biol. Chem. 2000; 275: 26976-26985Abstract Full Text Full Text PDF PubMed Google Scholar), et al. C. Biol. PubMed Scopus Google Scholar) that amino acid also caused the increased of ASNS mRNA in mRNA to the increase in ASNS mRNA in were in for to ASNS mRNA content and to either or MEM, ASNS RNA content was by qRT-PCR, and the rate of was was that the rate of mRNA was different in the presence or of and in the mRNA was h. that amino acid deprivation of cells the ASNS mRNA content by mRNA the in the transcription rate of the ASNS gene, the of ASNS were that are from during is a of to the data by nuclear analysis R. PubMed Scopus Google Scholar). cells were in for for a time course and for for a time analysis of ASNS with an was used to a transient the time course an increase in ASNS transcription rate was 2 of which a of the was a decline from 2 to h, the level was elevated with the the 2 were was that the ASNS transcription rate to increase of and to a of the 2 h. ATF3-FL, ATF4, and C/EBPβ to Amino the of ATF4, ATF3-FL, or C/EBPβ protein content amino acid limitation, cell from or cells were to Amino acid deprivation caused an of ATF4 and ATF3-FL proteins A and with the of ATF4 by amino acid H. R. 2000; Full Text Full Text PDF PubMed Scopus Google PubMed Scopus Google Scholar), ATF4 protein content was increased by 2 A and 4 h, and declined the to the the of ATF3-FL protein expression was and h, but for the of the A and The changes in C/EBPβ protein were The C/EBPβ mRNA and of that within the and are two different forms of activating whereas is a that as a H. J. PubMed Scopus Google Scholar). The are and for the human are known to and are to J. 2002; PubMed Google 2003; PubMed Scopus Google Scholar). a a human with the was in and the and with an that C/EBPβ the protein was as a of to was the was for a with a rate of the Biol. Google Scholar). The C/EBPβ-LAP as a of that to with the The in the cells during the course of deprivation the and the the were increased in following amino acid Although the amount of these protein forms was the increase was The for to but C/EBPβ is known to the of J. 2002; PubMed Google 2003; PubMed Scopus Google Scholar). or ATF4, ATF3-FL, or C/EBPβ protein content in the was of nuclear from or cells were also to Amino acid deprivation caused an of ATF4 and ATF3-FL proteins in the The increase in nuclear ATF4 content A and that in the cell that the initial increase in ATF4 protein is to the nuclear with the that ATF4 is a of amino the increase in nuclear ATF4 content closely paralleled the increased transcription rate of the ASNS gene the in the ATF3-FL protein level A and was to that in the cell and the ATF3 nuclear content correlated with the decline in transcription rate that between 4 and h. The initial changes in nuclear C/EBPβ protein and paralleled in the cell but the nuclear increase in A and was more transient with that in the cell with the increase in C/EBPβ A and a time the rate of transcription in was ATF4, ATF3-FL, and C/EBPβ ASNS Promoter studies have demonstrated that transient expression of ATF4 (3Siu F. Bain P.J. LeBlanc-Chaffin R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; 277: 24120-24127Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), C/EBPβ (5Siu F.Y. Chen C. Zhong C. Kilberg M.S. J. Biol. Chem. 2001; 276: 48100-48107Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar), or ATF3-FL (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar) in regulated transcription from a gene by the ASNS promoter. the temporal for expression of ATF4, C/EBPβ, and ATF3-FL proteins suggest that the ASNS promoter is The of ASNS by ATF4, ATF3-FL, and C/EBPβ was by different of the expression for ATF4, C/EBPβ, or ATF3-FL and the of protein content was by different of cells were with ATF4 of or of transcription was enhanced in a with a of the of ATF4 was with the ATF3-FL and C/EBPβ, the two factors in an of the of ATF4 the C/EBPβ amount from to but ATF3-FL in the ATF3-FL amount was to a of ASNS promoter was the ATF4 ASNS promoter was by the of ATF3-FL and C/EBPβ, but to a The amount of ATF3-FL to more C/EBPβ, in that of ATF3-FL the of the amount of with or of C/EBPβ was in the of a of ATF4 action was the that present ATF3-FL and C/EBPβ the activation of the ASNS promoter. of in with the ASNS Promoter during Amino and of RNA mobility shift analysis demonstrated that C/EBPβ, ATF4, and ATF3-FL are of binding to the NSRE-1 within the ASNS promoter (3Siu F. Bain P.J. LeBlanc-Chaffin R. Chen H. Kilberg M.S. J. Biol. Chem. 2002; 277: 24120-24127Abstract Full Text Full Text PDF PubMed Scopus (199) Google Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google F.Y. Chen C. Zhong C. Kilberg M.S. J. Biol. Chem. 2001; 276: 48100-48107Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). other of the ATF and C/EBP or ATF and C/EBP interaction with the ASNS promoter in during amino acid chromatin immunoprecipitation were using for ATF3-FL, ATF4, C/EBPβ, and A was used as of chromatin from cells in either or was by and electrophoresis of showed a as and showed that an in there was an increase in ATF3-FL, ATF4, and C/EBPβ binding to the promoter binding of RNA polymerase to the ASNS promoter during amino acid deprivation was also The increase in ASNS promoter binding by ATF and C/EBP pol and general transcription and in amino cells was by real-time analysis the other of the ATF and C/EBP binding of and a level to the the other and promoter binding was the and for there was in the level of binding between and cells and the amount of binding in the amino cells to elevated but the Although for the amino from the NSRE-1 to the rate of ASNS transcription and act in a to a response to the and unfolded protein response Kilberg M.S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). expression studies in cells demonstrated that the of transcription could by either or of these two the increase in transcription following amino acid Although the amount of binding to the ASNS promoter was different from the with the transient expression there was a amount of binding in cells in either or of the the ASNS Promoter During Amino the temporal association of pol and the general transcription with the ASNS cells were in either or for h, and analysis was with cells from time were the data to in cell between The that an increased association of pol with the ASNS promoter within to the and was a level the of the amino acid deprivation The cells in showed a minimal level of pol association the time the transcription rate was the the showed that the association of RNA pol with the ASNS promoter closely paralleled the increased transcription rate of ASNS with the binding for RNA pol II, the interaction of TFIIB and TATA-binding protein, of the general transcription increased in the amino cells during the of the and was a level analysis of the binding for general transcription showed association with the with the ASNS promoter in either or cells course of transcription factor binding to the ASNS promoter during amino acid deprivation. cells were in either the or for h. Chromatin immunoprecipitation analysis was using the ATF4, ATF3-FL, or from amino cells and from cells were as the to the with a of the of and the the of the The the rate of ASNS gene transcription from of to the ASNS Promoter with of During Amino is with chromatin and increased transcription PubMed Scopus Google Scholar). for the of amino acid deprivation chromatin of within the ASNS promoter was also an initial the of H3 and H4 was increased in amino cells with cells the time of A more time course showed a increase in histone H3 and H4 the promoter within of of from the The highly for the and of amino acid deprivation the of a that correlated to the changes for the transcription rate in the the other using that a of within the ASNS gene showed or histone of the the amino acid histone to to the promoter of the ASNS gene and correlated with activation of the showed to the ASNS promoter of proteins with known histone including or the of the histone that the ASNS gene following amino acid is an of amino acid that to of to the ASNS Promoter during Amino study the temporal association of ATF3-FL, ATF4, and C/EBPβ with the ASNS the time course of factor binding was cells to either or The minimal through the course of and showed between and cells the other immunoprecipitation of the ASNS promoter by ATF3-FL, ATF4, or C/EBPβ showed a elevated level of binding during amino acid deprivation with the the transcription factors a of promoter ATF4 a level of binding within 2 of amino acid and that level was the and ATF3-FL, increase in binding to the ASNS promoter was for the and binding during the amino acid deprivation a the transcription rate the is that the binding of ATF4 to the pol paralleled the elevated transcription whereas the association of ATF3-FL and C/EBPβ to with the decline in transcription rate the of ATF4 ASNS a time course of factor binding was to the time of association of ATF4, pol II, and H3 and H4 with the ASNS promoter. The established that of these proteins a elevated level of binding following amino acid deprivation that the association of ATF4 with the ASNS RNA pol and histone following amino acid deprivation. the transcription rate was time factor binding closely paralleled the increased transcription rate of the ASNS gene The data in the present study that the of ATF4, and C/EBPβ in human ASNS gene expression following amino acid deprivation. The protein content for ATF4 and ATF3-FL were increased during amino acid limitation, whereas C/EBPβ-LIP declined slightly. The total amount of C/EBPβ-LAP protein was unchanged, but changes in the distribution among multiple C/EBPβ-LAP forms were observed. with the known of ATF4 synthesis H. R. 2000; Full Text Full Text PDF PubMed Scopus Google PubMed Scopus Google Scholar), the increase in ATF4 protein that for ATF3-FL or the changes in overexpression of ATF3-FL and C/EBPβ the activation of the ASNS promoter. amino acid ATF4, and C/EBPβ with the ASNS promoter in a with binding of RNA polymerase and other general transcription analysis also demonstrated for the time the temporal changes in the chromatin in of histone following amino acid ChIP, a time course analysis of the 2 following amino acid revealed a binding of transcription with increased ATF4 of histone H3 and H4 and increased association of the general transcription complex closely the elevated transcription binding of ATF3-FL and C/EBPβ to the ASNS promoter and correlated with a decline in transcription data and the present have to a in for activation of the human ASNS gene in response to amino acid of amino acid response including is in the the of the is to is known but to The present the in for factor binding to an and the that ATF4 in activating the ASNS The also that there is a that in a activation of transcription factors as ATF3 and C/EBPβ, which to the activation of the ASNS gene and to a activated to the within the ATF4, a of the transcription factor to with a of RNA polymerase R. C. 2003; PubMed Scopus Google Scholar). ATF4 is enhanced by whereas used as a the of that ATF4 markedly ATF4 the present the temporal of ATF4 the of RNA polymerase II, and the transcription rate changes suggest that ATF4 is the factor that increased ASNS transcription amino acid The of ATF4 protein expression in the and declined the to the a to the of ASNS as a of transcription transcription factor binding and gene activation were limitation, ATF4 binding was increased and closely paralleled the in transcription The increase in ATF3-FL protein more 4 and for the of the The transcription analysis with the of ATF3-FL and C/EBPβ binding to the ASNS promoter that these two factors the activation of the ASNS promoter and to the transcription rate induced by amino acid The ATF3 protein a and of the bZIP of transcription ATF3-FL but also with and to binding to an or 2001; PubMed Scopus Google Scholar). The transcriptional are different ATF3-FL as a in which to act to or as a with other bZIP in which either or transcription Google Scholar). the cellular and ATF3 action established for The transient expression studies of ATF3-FL and C/EBPβ suggest C/EBPβ have a ATF4 is that ATF3-FL as the is with the of ATF3-FL to counterbalance ATF4 action (4Pan Y.-X. Chen H. Siu F. Kilberg M.S. J. Biol. Chem. 2003; 278: 38402-38412Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). the of ATF3-FL and C/EBPβ to transcriptional the activated ASNS by electrophoresis mobility shift analysis following et al. J. PubMed Scopus Google Scholar) a transient increase in ATF4 binding to the in the human promoter 2 h, which was 6 by ATF3 as transcription from the gene declined the expression also showed that ATF4 the gene through the and that ATF3 that The present data the of et al. J. PubMed Scopus Google Scholar) by that of in by to ASNS and CHOP, that as have for the amino acid Chen H. Kilberg M.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and the amino acid J. C. R. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). the of between NSRE-1 and the other is that transient activation of these by ATF4 and by as in a general for of these in response to a of cellular to other factors to ASNS the analysis and to the promoter in and amino acid conditions. association of these factors in the response to amino acid but the of to in the amino of the gene and to of binding to the in C. Biol. 2000; PubMed Scopus Google Scholar). et al. J. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that the of is an factor in action following amino acid deprivation. The present also demonstrated a in promoter histone during amino acid deprivation. is the that changes in amino acid status histone The of histone H3 and H4 the ASNS promoter were to for ATF4 and RNA pol association during amino acid deprivation. the other of either H3 or H4 is in the of the ASNS gene, the of is in with the that histone H3 is the of transcription of in human but is of the transcription C. PubMed Scopus Google Scholar). The of histone is to transcription by of to transcriptional or chromatin in 2002; PubMed Scopus Google Scholar). in studies that transcriptional have histone 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). a transcriptional and the to ATF4, to to of histone H3 and transcription activation 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of with as and PCAF, by a of transcription is known to and of the histone a temporal of ATF4 binding with of histone H3 and H4 the ASNS promoter following amino acid is that ATF4 as the factor for an to the ASNS promoter more to pol and the general transcription machinery. The in the for to the of the proteins that the proteins to the general transcription and the during the activated and the more of is to the or more that with the transcriptional the ASNS promoter and transcription of the for nutritional via the amino acid response other of the for and in of for in