人类沉默枢纽 (HUSH) 复合物对内源性逆转录元件的调控
中文名称
通路描述
人类沉默枢纽 (HUSH) 复合物由 MPHOSPH8 (MPP8)、Periphilin (PHPLN1) 和 TASOR 组成，似乎作为支架结合其他亚基 (参见 Seczynska 和 Lehner 2023)。HUSH 复合物优先抑制年轻 LINE1 逆转录元件 (Liu 等 2018, Robbez-Masson 等 2018) 和某些 HIV 整合物的转录。HUSH 复合物通过两种方式创建抑制性染色质 (参见 Seczynska 和 Lehner 2023)。首先，HUSH 可以通过结合已甲基化的 H3K9 和招募 SETDB1 来甲基化相邻核小体的 H3K9 (Tchasovnikarova 等 2015)。其次，HUSH 可以通过其 PHPLN1 亚基结合新生转录本，招募 SETDB1 在转录位点甲基化组蛋白 H3 的第 9 位赖氨酸 (H3K9) (Seczynska 等 2022)。通过未表征的机制，HUSH 复合物靶向长内含子缺失的 cDNA，如逆转录元件产生的，以及正常细胞基因的不寻常长外显子 (Seczynska 等 2022)。内含子通过某种方式保护免受 HUSH 的沉默，但实际剪接不是必需的 (Seczynska 等 2022)。在小鼠中，ZNF638 (NP220, Znf638 基因) 招募 HUSH 复合物到未整合的小鼠白血病病毒 (MLV) (Zhu 等 2018)，而在人类细胞中，ZNF638 (NP220) 和 HUSH 沉默重组腺相关病毒 (Das 等 2022)。ZNF638 招募 HUSH 到人类逆转录元件的潜在招募尚未得到证实。
英文描述
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex The Human Silencing Hub (HUSH) complex comprises MPHOSPH8 (MPP8), Periphilin (PHPLN1), and TASOR, which appears to act as a scaffold that binds the other subunits (reviewed in Seczynska and Lehner 2023). The HUSH complex preferentially represses transcription of young LINE1 retroelements (Liu et al. 2018, Robbez-Masson et al. 2018) and some HIV integrants (Tchasovnikarova et al. 2015, Zhu et al. 2018, Chougui and Margottin-Goguet 2019).
The HUSH complex creates repressive chromatin in two ways (reviewed in Seczynska and Lehner 2023). Firstly, HUSH can cause spreading of existing heterochromatin by binding existing trimethylated H3K9 and recruiting SETDB1 to trimethylate H3K9 of adjacent nucleosomes (Tchasovnikarova et al. 2015). Secondly, HUSH can initiate heterochromatin by binding nascent transcripts via its PHPLN1 subunit and recruiting SETDB1 to trimethylate lysine-9 of histone H3 (H3K9) at the locus being transcribed (Seczynska et al. 2022).
By an uncharacterized mechanism, the HUSH complex targets long intronless cDNAs, such as those produced by retroelements, as well as unusually long exons of normal cellular genes (Seczynska et al. 2022). Introns somehow protect against silencing by HUSH, though actual splicing is not required (Seczynska et al. 2022). In mice, ZNF638 (NP220, Znf638 gene) recruits the HUSH complex to unintegrated murine leukemia virus (MLV) (Zhu et al. 2018) and in human cells ZNF638 (NP220) and HUSH silence recombinant adeno-associated viruses (Das et al. 2022). The potential recruitment of HUSH by ZNF638 to human retroelements is not yet demonstrated.
The HUSH complex creates repressive chromatin in two ways (reviewed in Seczynska and Lehner 2023). Firstly, HUSH can cause spreading of existing heterochromatin by binding existing trimethylated H3K9 and recruiting SETDB1 to trimethylate H3K9 of adjacent nucleosomes (Tchasovnikarova et al. 2015). Secondly, HUSH can initiate heterochromatin by binding nascent transcripts via its PHPLN1 subunit and recruiting SETDB1 to trimethylate lysine-9 of histone H3 (H3K9) at the locus being transcribed (Seczynska et al. 2022).
By an uncharacterized mechanism, the HUSH complex targets long intronless cDNAs, such as those produced by retroelements, as well as unusually long exons of normal cellular genes (Seczynska et al. 2022). Introns somehow protect against silencing by HUSH, though actual splicing is not required (Seczynska et al. 2022). In mice, ZNF638 (NP220, Znf638 gene) recruits the HUSH complex to unintegrated murine leukemia virus (MLV) (Zhu et al. 2018) and in human cells ZNF638 (NP220) and HUSH silence recombinant adeno-associated viruses (Das et al. 2022). The potential recruitment of HUSH by ZNF638 to human retroelements is not yet demonstrated.
所含基因
39 个基因
ATF7IP
EHMT1
EHMT2
H2AFB1
H2AFJ
H2AFV
H2AFX
H2BFS
H3F3A
HIST1H2AB
HIST1H2AC
HIST1H2AD
HIST1H2AJ
HIST1H2BA
HIST1H2BB
HIST1H2BC
HIST1H2BD
HIST1H2BH
HIST1H2BJ
HIST1H2BK
HIST1H2BL
HIST1H2BM
HIST1H2BN
HIST1H2BO
HIST1H3A
HIST1H4
HIST2H2AA3
HIST2H2AC
HIST2H2BE
HIST2H3A
HIST3H2BB
MORC2
MPHOSPH8
PPHLN1
RBM7
SETDB1
SKIV2L2
TASOR
ZCCHC8