Shaklai Sigal, Somech Raz, Gal-Yam Einav Nili, Deshet-Unger Naamit, Moshitch-Moshkovitz Sharon, Hirschberg Koret, Amariglio Ninette, Simon Amos J, Rechavi Gideon
Sheba Cancer Research Center and the Institute of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
Eur J Cell Biol. 2008 May;87(5):267-78. doi: 10.1016/j.ejcb.2008.01.014. Epub 2008 Apr 9.
Proteins of the nuclear envelope have been implicated as participating in gene silencing. BAF, a DNA- and LEM domain-binding protein, has been suggested to link chromatin to the nuclear envelope. We have previously shown that LAP2beta, a LEM-domain inner nuclear membrane protein, represses transcription through binding to HDAC3 and induction of histone H4 deacetylation. We now show that LAP2zeta, the smallest LAP2 family member, is also involved in regulation of transcription. We show that similar to other LEM-domain proteins LAP2zeta interacts with BAF. LAP2zeta-YFP and BAF co-localize in the cytoplasm, and overexpression of LAP2zeta leads to reduction of nucleoplasmic BAF. Mutations in the LAP2zeta-YFP LEM domain decrease its interaction with BAF retaining the nucleo-cytoplasmic distribution of BAF. Co-expression of LAP2beta and LAP2zeta results in inhibition of LAP2beta-induced gene silencing while overexpression of LAP2zeta alone leads to a small increase in transcriptional activity of various transcription factors. Our results suggest that LAP2zeta is a transcriptional regulator acting predominantly to inhibit LAP2beta-mediated repression. LAP2zeta may function by decreasing availability of BAF. These findings could have implications in the study of nuclear lamina-associated diseases and BAF-dependent retroviral integration.
核被膜蛋白被认为参与基因沉默。BAF是一种与DNA和LEM结构域结合的蛋白,有人提出它能将染色质与核被膜连接起来。我们之前已经表明,LAP2β是一种LEM结构域的内核膜蛋白,它通过与HDAC3结合并诱导组蛋白H4去乙酰化来抑制转录。我们现在表明,LAP2ζ是LAP2家族中最小的成员,也参与转录调控。我们发现,与其他LEM结构域蛋白类似,LAP2ζ与BAF相互作用。LAP2ζ-YFP和BAF共定位于细胞质中,LAP2ζ的过表达导致核质中BAF减少。LAP2ζ-YFP的LEM结构域突变会降低其与BAF的相互作用,同时保持BAF的核质分布。LAP2β和LAP2ζ的共表达会抑制LAP2β诱导的基因沉默,而单独过表达LAP2ζ会导致各种转录因子的转录活性略有增加。我们的结果表明,LAP2ζ是一种转录调节因子,主要作用是抑制LAP2β介导的抑制作用。LAP2ζ可能通过降低BAF的可用性来发挥作用。这些发现可能对核纤层相关疾病和BAF依赖性逆转录病毒整合的研究有影响。