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The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1β and the heterochromatin protein HP1

Delphine Quénet^*, Véronique Gasser^*, Laetitia Fouillen, Florence Cammas, Sarah Sanglier-Cianferani, Régine Losson and Françoise Dantzer^*,1

^* Département Intégrité du Génome, UMR7175, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France;

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; and

Laboratoire de Spectrométrie de Masse Bio-organique, UMR7178, Ecole de Chimie, Polymères et Matériaux, Strasbourg, France

¹Correspondence: Département IDG, UMR7175, ESBS, Bld. S. Brant, 67412 Illkirch, France. E-mail: fdantzer{at}esbs.u-strasbg.fr

Recent advances reveal emerging unique functions of poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 in heterochromatin integrity and cell differentiation. However, the chromatin-mediated molecular and cellular events involved remain elusive. Here we describe specific physical and functional interactions of Parp-1 and Parp-2 with the transcriptional intermediary factor (TIF1β) and the heterochromatin proteins (HP1) that affect endodermal differentiation. We show that Parp-2 binds to TIF1β with high affinity both directly and through HP1. Both partners colocalize at pericentric heterochromatin in primitive endoderm-like cells. Parp-2 also binds to HP1β but not to HP1. In contrast Parp-1 binds weakly to TIF1β and HP1β only. Both Parps selectively poly(ADP-ribosyl)ate HP1. Using shRNA approaches, we provide evidence for distinct participation of both Parps in endodermal differentiation. Whereas Parp-2 and its activity are required for the relocation of TIF1β to heterochromatic foci during primitive endodermal differentiation, Parp-1 and its activity modulate TIF1β-HP1 association with consequences on parietal endodermal differentiation. Both Parps control TIF1β transcriptional activity. In addition, this work identifies both Parps as new modulators of the HP1-mediated subcode histone.—Quénet, D., Gasser, V., Fouillen, L., Cammas, F., Sanglier-Cianferani, S., Losson, R., Dantzer, F. The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1β and the heterochromatin protein HP1.

Key Words: epigenetics • pericentric heterochromatin • post-translational modification • protein interactions