Tumor suppressor genes are larger than apoptosis-effector genes and have more regions of active chromatin: Connection to a stochastic paradigm for sequential gene expression programs

Apoptosis- and proliferation-effector genes are substantially regulated by the same transactivators, with E2F-1 and Oct-1 being notable examples. The larger proliferation-effector genes have more binding sites for the transactivators that regulate both sets of genes, and proliferation-effector genes have more regions of active chromatin, i.e, DNase I hypersensitive and histone 3, lysine-4 trimethylation sites. Thus, the size differences between the 2 classes of genes suggest a transcriptional regulation paradigm whereby the accumulation of transcription factors that regulate both sets of genes, merely as an aspect of stochastic behavior, accumulate first on the larger proliferation-effector gene “traps,” and then accumulate on the apoptosis effector genes, thereby effecting sequential activation of the 2 different gene sets. As IRF-1 and p53 levels increase, tumor suppressor proteins are first activated, followed by the activation of apoptosis-effector genes, for example during S-phase pausing for DNA repair. Tumor suppressor genes are larger than apoptosis-effector genes and have more IRF-1 and p53 binding sites, thereby likewise suggesting a paradigm for transcription sequencing based on stochastic interactions of transcription factors with different gene classes. In this report, using the ENCODE database, we determined that tumor suppressor genes have a greater number of open chromatin regions and histone 3 lysine-4 trimethylation sites, consistent with the idea that a larger gene size can facilitate earlier transcriptional activation via the inclusion of more transactivator binding sites.

细胞凋亡效应基因与增殖效应基因均受同一类反式激活因子（transactivators）的显著调控，其中以E2F-1与Oct-1为典型代表。相较于凋亡效应基因，尺寸更大的增殖效应基因携带更多调控两类基因的反式激活因子结合位点，且增殖效应基因拥有更多活跃染色质区域，即脱氧核糖核酸酶I（DNase I）超敏感位点以及组蛋白H3赖氨酸4三甲基化（histone 3 lysine-4 trimethylation）位点。因此，两类基因的尺寸差异提示存在一种转录调控范式：调控两类基因的转录因子仅作为随机行为的一部分，其积累过程会优先结合更大的增殖效应基因“捕获位点”，随后再结合凋亡效应基因，从而实现两类不同基因集的顺序激活。随着干扰素调节因子1（IRF-1）与p53的表达水平升高，肿瘤抑制蛋白会首先被激活，随后才会激活凋亡效应基因——这一过程例如发生在DNA修复的S期停滞阶段。肿瘤抑制基因的尺寸大于凋亡效应基因，且携带更多IRF-1与p53结合位点，这同样提示了一种基于转录因子与不同基因类别间随机相互作用的转录时序调控范式。本研究利用ENCODE数据库（Encyclopedia of DNA Elements）分析后发现，肿瘤抑制基因拥有更多的开放染色质区域与组蛋白H3赖氨酸4三甲基化位点，这与“更大的基因尺寸可通过包含更多反式激活因子结合位点，促进转录的提前激活”这一假说相符。