Kolodziej Stephan, Kuvardina Olga N, Oellerich Thomas, Herglotz Julia, Backert Ingo, Kohrs Nicole, Buscató Estel la, Wittmann Sandra K, Salinas-Riester Gabriela, Bonig Halvard, Karas Michael, Serve Hubert, Proschak Ewgenij, Lausen Jörn
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany.
Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Nat Commun. 2014 May 29;5:3995. doi: 10.1038/ncomms4995.
The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.
转录因子Tal1是造血和白血病中基因表达的关键激活剂或抑制剂。Tal1对不同基因转录产生差异影响的机制尚未完全明确。在此，我们表明Tal1与肽基精氨酸脱亚氨酶IV（PADI4）相互作用。我们证明PADI4可通过影响H3R2me2a作为一种表观遗传共激活剂。在Tal1/PADI4靶基因IL6ST处，由PRMT6触发的抑制性H3R2me2a标记被PADI4抵消，PADI4增强了活性H3K4me3标记，从而增加IL6ST表达。相反，在CTCF启动子处，PADI4起抑制作用。我们提出PADI4对IL6ST转录的影响在造血干/祖细胞谱系分化过程中对IL6ST表达的控制中发挥作用。这些结果为在白血病中对Tal1进行药理学调控提供了可能性。
