瘤抑制基因p15的表观遗传沉默由其反意义RNA沉默
Wenqiang Yu1, David Gius, Patrick Onyango
1Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
Nature
|January 11, 2008
概括
自然的反意义RNA可以使瘤抑制基因 (TSG) 沉默,就像癌症中的p15. 这一过程涉及色素的形成和DNA甲基化,可能会在瘤发生过程中触发基因沉默.
科学领域:
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症生物学 癌症生物学
背景情况:
- 瘤抑制基因 (TSG) 对于抑制细胞生长至关重要,并且在癌症中经常被表观遗传性沉默.
- 虽然DNA甲基化是TSG沉默的已知机制,但非编码RNA,特别是反意义RNA的作用越来越被认可.
- 反感性RNA可以与它们的感性对应物相互作用,影响基因表达和表观遗传修饰.
研究的目的:
- 调查自然反感RNA在癌症中瘤抑制基因表观遗传沉默中的作用.
- 阐明抗意义RNA,特别是p15AS,在白血病中沉默p15基因的机制.
- 为了确定反感性RNA是否可以启动异色染色体的形成和DNA甲基化导致TSG沉默.
主要方法:
- 在白血病样本中分析p15反感 (p15AS) 和p15感觉表达.
- 生成一个p15AS表达结构,研究它对cis和trans中的p15沉默的影响.
- 用甲基化和异色染色素抑制剂治疗,以评估它们对p15AS诱导的沉默的影响.
- 在小鼠胚胎干细胞中表达外源的p15AS,以评估其对p15沉默和细胞生长的影响.
主要成果:
- 在白血病中观察到p15AS和p15感官表达之间的反向相关性.
- 一个p15AS表达构造诱导了p15通过异色染色体形成的沉默,最初独立于DNA甲基化.
- 即使在p15AS表达停止后,诱导的沉默仍然存在,但在抑制剂下是可逆的.
- 在小鼠胚胎干细胞中表达外源的p15AS导致p15沉默和增长,随后在分化后进行DNA甲基化.
结论:
- 自然的反感RNAs,如p15AS,可以起到催化剂的作用,对异性染色素的形成和DNA甲基化.
- 反意义RNA介导的TSG沉默是瘤发生的一个重要机制.
- 这项研究突出了表观遗传调节和TSG无活化在癌症发展中的新途径.
相关概念视频
01:22MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends...
02:30siRNA - Small Interfering RNAs
Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:22MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...