Abstract
<title>Abstract</title> <p> Sumoylation consists of the covalent attachment of the SUMO polypeptide to proteins and is essential in mammals, in which it controls virtually all cellular processes. The specific SUMO proteases of the SENP family are key regulators of the process. Among them, SENP7 and SENP6 are unique in having a split catalytic domain involved in depolymerizing SUMO2/3 polySUMO chains. Besides, they have long N-terminal regions poorly studied to date. In this study, we have analyzed cells lacking SENP7 to investigate alterations in the transcription profile and chromatin structure. Interestingly, we observe a significant downregulation of development-related genes, especially those associated with the nervous system, and a modest upregulation of chromosome X genes. This correlates with disturbed DNA compaction and histone modification profile. In the <italic>SENP7</italic> knockout background, we have stably expressed the catalytic domain alone, which notably rescues the expression of developmental genes and restores DNA compaction and the histone modification profile. However, it does not suffice to reestablish the expression of chromosome X genes, uncovering a relevant role for SENP7 in chromosome X architecture, which absolutely requires its N-terminal region. Remarkably, the levels of two key players of chromosome X inactivation, the long non-coding RNA <italic>XIST</italic> and the histone variant macroH2A, which are downregulated in knockout cells, do not recover in the stable cell line expressing the catalytic domain. Thus, we propose a dual role for SENP7. For an important set of developmental genes, its isopeptidase activity facilitates chromatin opening, while for another set of genes, its N-terminal region is required for the stabilization of a repressive state, which is particularly manifest in chromosome X. </p>