Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload
Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload
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DOI：
10.1152/ajpheart.01111.2005
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发表时间：
2006-06-01
影响因子：
4.8
通讯作者：
Baldwin, KM
中科院分区：
文献类型：
--
作者：
Haddad, F;Qin, AX;Baldwin, KM
高血压已被证明会导致心脏肥大和肌球蛋白重链（MHC）基因表达从更快的α-MHC亚型向更慢的β- MHC亚型的转变。在正常对照（NC）和12天压力超负荷（AbCon）心脏的三个区域中分析β-和α- MHC前mRNA、mRNA以及新发现的反义β- RNA的表达：左心室心尖、左心室基部和隔膜。AbCon心脏中的RNA分析靶向每个RNA分子的5 '和3 '末端。在所有三个区域中，β-MHCmRNA表达相对于对照显著增加，无论靶位点（5 '或3 ;末端）如何。相反，在AbCon心脏中α- MHC前mRNA的表达依赖于测量的位点（5 '端对3 '端）.例如，当靶向3 '末端（最后一个内含子）时，前mRNA没有变化，而当测量靶向25- kb分子的5 '末端（第二个内含子）时，前mRNA在AbCon心脏中显著增加.对反义β- RNA的分析显示，无论其测量位点如何，其在AbCon心脏中的表达相对于对照显著降低。反义β- RNA与β-mRNA表达呈负相关（P < 0.05），提示反义RNA对正义β- MHC基因表达有抑制作用。而反义β- RNA与α- MHC前体mRNA表达呈正相关（P < 0.05）.后一观察结果沿着β- MHC基因相对于β-反义的位置，提示α- MHC正义和β-反义转录可能通过共同的基因间调节序列共同调节.我们的研究结果表明，在AbCon心脏中β- MHC表达的增加不仅是β- MHC转录增加的结果，而且还涉及反义β- RNA调控方案。尽管关于反义调控的确切机制尚不清楚，但它可能涉及β- MHC基因的转录活性和转录后加工的调节。
Hypertension has been shown to cause cardiac hypertrophy and a shift in myosin heavy chain ( MHC) gene expression from the faster alpha- to slower beta- MHC isoform. The expression of the beta- and alpha- MHC pre- mRNAs, mRNAs, as well as the newly discovered antisense beta- RNA were analyzed in three regions of the normal control ( NC) and 12- day pressure- overloaded ( AbCon) hearts: the left ventricle apex, left ventricle base, and the septum. The RNA analyses in the AbCon heart targeted both the 5 ' and the 3 ' ends of each RNA molecule. beta- MHC mRNA expression significantly increased relative to control in all three regions, regardless of the target site ( 5 ' or 3 ; end). In contrast, alpha- MHC pre- mRNA expression in the AbCon heart depended on the site of the measurement ( 5 ' vs. 3 ' end). For example, whereas the pre- mRNA did not change when targeted at the 3 ' end ( last intron), it increased significantly in the AbCon heart when measurement targeted the 5 ' end ( 2nd intron) of the 25- kb molecule. Analyses of the antisense beta- RNA revealed that its expression in the AbCon heart was significantly decreased relative to control regardless of its measurement site. A negative correlation was observed between the beta- mRNA expression and the antisense beta- RNA ( P < 0.05), suggesting an inhibitory role of antisense RNA on the sense beta- MHC gene expression. In contrast, a positive correlation was observed between the antisense beta- RNA and the alpha- MHC pre- mRNA ( P < 0.05). This latter observation along with the beta- MHC gene position relative to that of the beta- antisense suggest that the alpha- MHC sense and beta- antisense transcription are coregulated likely via common intergenic regulatory sequences. Our results suggest that the increased beta- MHC expression in the AbCon heart not only is the result of increased beta- MHC transcription but also involves an antisense beta- RNA regulation scheme. Although the exact mechanism concerning antisense regulation is not clear, it could involve modulation of both transcriptional activity of the beta- MHC gene and posttranscriptional processing.