Biology subjects

Collette, J. R.

Publications and source records attributed to Collette, J. R..

2 recordsLinked to original sources

bioRxiv2026

NSD3 stabilizes nuclear compartmentalization and promotes megabase-scale chromatin interactions

Identifying biomolecules that shape nuclear organization is essential for understanding gene regulation in health and disease. Oncogenic fusion proteins rewire chromosome folding and generate biomolecular condensates, but the cofactors of oncoprotein-driven chromatin regulation remain poorly defined, and whether such factors have analogous functions in fusion-naive cells is unknown. We find that NSD3 mediates chromosome folding in fusion-positive and fusion-negative cells. NSD3 stabilizes the BRD4-NUT fusion oncoprotein on chromatin, promotes histone H3K36me2, and supports oncogene expression while maintaining BRD4-NUT nuclear condensates. NSD3 loss attenuates distant chromatin interactions between BRD4-NUT megadomains both within and between chromosomes. In cells lacking BRD4-NUT, the short, catalytically inactive isoform of NSD3, NSD3short, promotes chromatin contacts separated by multiple megabases. The ability of NSD3short to promote long-range chromatin contacts requires its PWWP domain. By combining chromatin structural analyses in fusion-positive and fusion-negative cells, we show that interrogating fusion oncoprotein-driven chromosome misfolding reveals the multicomponent basis of nuclear compartmentalization and uncovers an adaptor protein that promotes chromatin contacts independent of enzymatic activity.

molecular biology↗

bioRxiv2019

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

cell biology↗