@article {162687, title = {Fibrillarin regulates epithelial integrity via EZH2-mediated modulation of scribble expression.}, journal = {Cell Rep}, volume = {44}, year = {2025}, month = {2025 Nov 25}, pages = {116608}, abstract = {

Fibrillarin (FBL) is a nucleolar protein critical for rRNA biogenesis. We show that FBL is essential for the maintenance of epithelial integrity through its regulation of cell-cell adhesion proteins. RNA-seq analyses upon FBL depletion revealed deregulation of adhesion- and apical membrane organization-associated pathways. FBL loss deregulates cell polarity via increased deposition of H3K27me3 on the SCRIB promoter, driven by the localization of a subpopulation of EZH2 from the nucleolus to the nucleoplasm. Disrupting the FBL-EZH2 interaction increases cell migration, underscoring a requirement for retaining EZH2 also in the nucleolus. Furthermore, FBL depletion induces EMT in breast epithelial cells, owing to increased levels of mesenchymal factors (Snail1, Twist1, and Zeb1) and activation of Akt. Since Scribble tethers PHLPP1 and PTEN to antagonize Akt, repression of Scribble induces EMT. In summary, FBL safeguards epithelial integrity, by regulating the expression of Scribble, uncovering an FBL-EZH2 axis in EMT and metastasis.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2025.116608}, author = {Saha, Santam and A K, Balaji and Meel, Sweety and Notani, Dimple and Sengupta, Kundan} } @article {91470, title = {An interdependent network of functional enhancers regulates transcription and EZH2 loading at the INK4a/ARF locus.}, journal = {Cell Rep}, volume = {34}, year = {2021}, month = {2021 Mar 23}, pages = {108898}, abstract = {

The INK4a/ARF locus encodes important cell-cycle regulators p14, p15, and p16. The neighboring gene desert to this locus is the most reproducible GWAS hotspot that harbors one of the densest enhancer clusters in the genome. However, how multiple enhancers that overlap with GWAS variants regulate the INK4a/ARF locus is unknown, which is an important step in linking genetic variation with associated diseases. Here, we show that INK4a/ARF promoters interact with a subset of enhancers in the cluster, independent of their H3K27ac and eRNA levels. Interacting enhancers transcriptionally control each other and INK4a/ARF promoters over long distances as an interdependent single unit. The deletion of even a single interacting enhancer results in an unexpected collapse of the entire enhancer cluster and leads to EZH2 enrichment on promoters in an ANRIL-independent manner. Dysregulated genes genome-wide mimic 9p21-associated diseases under these scenarios. Our results highlight intricate dependencies of promoter-interacting enhancers on each other.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2021.108898}, author = {Farooq, Umer and Saravanan, Bharath and Islam, Zubairul and Walavalkar, Kaivalya and Singh, Anurag Kumar and Jayani, Ranveer Singh and Meel, Sweety and Swaminathan, Sudha and Notani, Dimple} } @article {71098, title = {Ligand dependent gene regulation by transient ERα clustered enhancers.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 Jan 06}, pages = {e1008516}, abstract = {

Unliganded Estrogen receptor alpha (ERα) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERα binds to several EREs relatively proximal to the pre-marked, or persistent, ERα-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERα-bound sites, forming Ligand Dependent ERα Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERα condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERα. Our results establish, at TFF1 and NRIP1 locus, a direct link between ERα condensates, ERα enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008516}, author = {Saravanan, Bharath and Soota, Deepanshu and Islam, Zubairul and Majumdar, Sudeshna and Mann, Rajat and Meel, Sweety and Farooq, Umer and Walavalkar, Kaivalya and Gayen, Srimonta and Singh, Anurag Kumar and Hannenhalli, Sridhar and Notani, Dimple} }