Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure

Marie-Therese El-Daher; Nicolas Cagnard; Marine Gil; Marie Chansel Da Cruz; Claire Leveau; Fernando Sepulveda; Mohammed Zarhrate; Frédéric Tores; Patricia Legoix; Sylvain Baulande; Jean Pierre de Villartay; Geneviève Almouzni; Jean-Pierre Quivy; Alain Fischer; Geneviève de Saint Basile

doi:10.1038/s41421-018-0061-y

Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure

Cell Discov. 2018 Nov 13:4:61. doi: 10.1038/s41421-018-0061-y. eCollection 2018.

Authors

Marie-Therese El-Daher^{1

2}, Nicolas Cagnard^{2

3

4}, Marine Gil¹, Marie Chansel Da Cruz^{2

5}, Claire Leveau^{1

2}, Fernando Sepulveda^{1

2}, Mohammed Zarhrate⁶, Frédéric Tores³, Patricia Legoix⁷, Sylvain Baulande⁷, Jean Pierre de Villartay^{2

5}, Geneviève Almouzni^{8

9}, Jean-Pierre Quivy^{8

9}, Alain Fischer^{2

10

11

12}, Geneviève de Saint Basile^{1

2

13}

Affiliations

¹ 1Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris, France.
² 2Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris, France.
³ 3Bioinformatic Platform, INSERM UMR 1163, Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris, France.
⁴ 4Structure Fédérative de Recherche (SFR) Necker, INSERM US24/CNRS UMS 3633, Paris, France.
⁵ 5Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Paris, France.
⁶ 6Genomic Platform, INSERM UMR 1163, Imagine Institute, Paris, France.
⁷ 7ICGex Next-Generation Sequencing Platform, , Curie Institute, Paris, France.
⁸ 8CNRS UMR3664, Curie Institute, PSL Research University, Paris, France.
⁹ 9Université Sorbonne, Pierre et Marie Curie (UPMC), Paris, France.
¹⁰ 10Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades Immunology and Pediatric Hematology Department, Paris, France.
¹¹ 11Collège de France, Paris, France.
¹² INSERM UMR1163, Paris, France.
¹³ 13Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Centre d'Etudes des Déficits Immunitaires, Paris, France.

Abstract

A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status.