Abstract
Changes in the peripheral distribution and amount of condensed chromatin are observed in a number of diseases linked to mutations in the lamin A protein of the nuclear envelope. We postulated that lamin A interactions with nuclear envelope transmembrane proteins (NETs) that affect chromatin structure might be altered in these diseases and so screened thirty-one NETs for those that promote chromatin compaction as determined by an increase in the number of chromatin clusters of high pixel intensity. One of these, NET23 (also called STING, MITA, MPYS, ERIS, Tmem173), strongly promoted chromatin compaction. A correlation between chromatin compaction and endogenous levels of NET23/STING was observed for a number of human cell lines, suggesting that NET23/STING may contribute generally to chromatin condensation. NET23/STING has separately been found to be involved in innate immune response signaling. Upon infection cells make a choice to either apoptose or to alter chromatin architecture to support focused expression of interferon genes and other response factors. We postulate that the chromatin compaction induced by NET23/STING may contribute to this choice because the cells expressing NET23/STING eventually apoptose, but the chromatin compaction effect is separate from this as the condensation was still observed when cells were treated with Z-VAD to block apoptosis. NET23/STING-induced compacted chromatin revealed changes in epigenetic marks including changes in histone methylation and acetylation. This indicates a previously uncharacterized nuclear role for NET23/STING potentially in both innate immune signaling and general chromatin architecture.
Highlights
The wide range of functions recently ascribed to the nuclear envelope (NE), the double membrane system surrounding the nucleus, indicates that it is a major signaling node for the cell [1,2]
NET23/STING was previously linked to functions in innate immune signaling and apoptosis [42,43,46], though these two roles were not linked
The role we have shown here for NET23/STING in promoting epigenetic changes and an intermediate chromatin condensation state that is frequently associated with subsequent apoptosis provides a possible means to link these disparate functions
Summary
The wide range of functions recently ascribed to the nuclear envelope (NE), the double membrane system surrounding the nucleus, indicates that it is a major signaling node for the cell [1,2]. One of these functions appears to be the organization of chromatin. In cells from patients with NE-linked progeria, mandibuloacral dysplasia, and lipodystrophy the dense chromatin partly or completely dissipates [9,10,11] In addition to these ultrastructural observations, changes in the distribution of epigenetic silencing marks were found in cells from patients with NE diseases and in tissue culture cells expressing disease mutations [12,13,14], leading to the idea that loss of this silencing function at the NE might alter gene expression to yield the disease pathologies. Changes in gene expression were found in patients with NE-linked muscular dystrophy and were recapitulated in a mouse model for this disease [15,16]
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