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A non-canonical EZH2/TRIM28 epigenetic axis drives heparan sulfate remodeling and melanoma metastasis

ABSTRACT: Melanoma progression is driven not only by oncogenic alterations but also by epigenetic programs that remodel the tumor microenvironment. Heparan sulfate (HS) proteoglycans are extracellular matrix components that control growth factor signaling and cell-matrix interactions, yet how chromatin-associated factors regulate HS remodeling in cancer remains ill-defined. Here, we identify the histone methyltransferase EZH2 as a regulator of HS biosynthesis in melanoma. Bioinformatic and genomic analyses reveal enrichment of EZH2 and additional Polycomb Repressive Complex (PRC) factors at regulatory regions of HS biosynthetic genes. CRISPR-mediated loss of EZH2 modulates expression of multiple HS-modifying enzymes, notably the secreted endosulfatases SULF1 and SULF2, enhancing HS 6-O sulfation and altering ligand binding at the cell surface. Unexpectedly, EZH2 promotes SULF1 through a methyltransferase-independent, non-canonical interaction with TRIM28, whereas SULF2 is repressed through canonical PRC2 activity. Functionally, SULF1 depletion impairs melanoma cell migration and invasion and reduces spontaneous metastasis in vivo. These findings define an epigenetic axis linking chromatin regulation to glycan remodeling and identify HS-modifying enzymes as candidate targets to limit melanoma metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313495 | GEO | 2026/09/18

REPOSITORIES: GEO

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A non-canonical EZH2/TRIM28 epigenetic axis drives heparan sulfate remodeling and melanoma metastasis [ChIP-Seq]

Project description:Melanoma progression is driven not only by oncogenic alterations but also by epigenetic programs that remodel the tumor microenvironment. Heparan sulfate (HS) proteoglycans are extracellular matrix components that control growth factor signaling and cell-matrix interactions, yet how chromatin-associated factors regulate HS remodeling in cancer remains ill-defined. Here, we identify the histone methyltransferase EZH2 as a regulator of HS biosynthesis in melanoma. Bioinformatic and genomic analyses reveal enrichment of EZH2 and additional Polycomb Repressive Complex (PRC) factors at regulatory regions of HS biosynthetic genes. CRISPR-mediated loss of EZH2 modulates expression of multiple HS-modifying enzymes, notably the secreted endosulfatases SULF1 and SULF2, enhancing HS 6-O sulfation and altering ligand binding at the cell surface. Unexpectedly, EZH2 promotes SULF1 through a methyltransferase-independent, non-canonical interaction with TRIM28, whereas SULF2 is repressed through canonical PRC2 activity. Functionally, SULF1 depletion impairs melanoma cell migration and invasion and reduces spontaneous metastasis in vivo. These findings define an epigenetic axis linking chromatin regulation to glycan remodeling and identify HS-modifying enzymes as candidate targets to limit melanoma metastasis.

2026-09-18 | GSE317470 | GEO

To examine the expression of Sulf1 and Sulf2, as well as other glycan-related genes, in human Idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples

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2011-09-05 | E-GEOD-31934 | biostudies-arrayexpress

Transcriptional control of Sulf1 by WT1 primes epicardial signalling and fate by modifying extracellular heparan sulfate status [scRNA-Seq]

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Heparan sulfate Sulfatases are essential for the patterning of stem cell–derived midbrain dopaminergic neurons

Project description:Midbrain dopaminergic (mDA) neuron loss underlies Parkinson’s disease (PD), making it critical to understand how mDA identity is established during development for cell replacement therapy. While intrinsic transcriptional programs and morphogen gradients driving mDA are known, the contribution of extracellular modulators remains less explored. Here, we show that the heparan sulfate (HS)–modifying enzymes SULF1 and SULF2 are essential for proper mDA neuron differentiation in vitro. Using CRISPR/Cas9-engineered human iPSCs, we demonstrate that SULF1/2 double knockout (DKO) cells fail to acquire ventral midbrain identity and instead adopt dorso-caudal fates, marked by ectopic expression of CDX2, HOX genes, neural crest, and Schwann cell markers. Mechanistically, SULF1/2 loss leads to increased 6-O-sulfation of HS chains, enhancing FGF signaling. FGF inhibition in SULF1/2 DKO cells suppresses CDX2+ axial progenitors and caudal derivatives, but does not completely restore ventral midbrain identity. Instead, it redirects cells toward dorsal lineages, including the emergence of ependymal-like cells. Our findings identify SULF1/2 as key modulators of anterior-posterior and dorsal-ventral patterning during mDA neuron development, possibly acting through a tight control of signaling molecules balance, and offer insights to refine differentiation protocols for PD cell therapy.

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2011-09-06 | GSE31934 | GEO

Transcriptional control of Sulf1 by WT1 primes epicardial signalling and fate by modifying extracellular heparan sulfate status [ATAC-Seq]

Project description:Considering the transcriptional correlations we observed between WT1 and 6-O-endosulfatases in the epicardium, we sought to elucidate whether WT1 regulates 6-O-endosulfatase expression directly and how its binding may differ between Sulf1 and Sulf2 in the epicardium. We first assessed the landscape of chromatin accessibility in FACS sorted epicardial cells at E13.5 (CD31-tdTomato+PDPN+), and employed TOBIAS footprinting to identify candidate WT1 binding sites in the Sulf1 and Sulf2 loci. This analysis predicted WT1 binding to the highly accessible Sulf1 promoter but no binding was predicted for Sulf2. As expected, there was lower accessibility in this locus which reflected reduced Sulf2 gene activity in the epicardial layer.

2026-08-06 | GSE299995 | GEO

Heparan sulfate Sulfatases are essential for the patterning of human stem cell-derived midbrain dopaminergic neurons

Project description:Midbrain dopaminergic neurons (mDA) are selectively lost in Parkinson’s disease (PD), driving sustained efforts to generate bona fide mDA neurons from human-induced pluripotent stem cells (iPSCs) for replacement therapy. While morphogen gradients and transcription factors have been extensively studied, extracellular regulators remain largely overlooked. Here, we identify the heparan sulfate-modifying enzymes SULF1 and SULF2 as essential for establishing mDA neuron identity in vitro. Using CRISPR/Cas9-engineered iPSCs, we show that loss of SULF1/2 increases 6-O-sulfation of heparan sulfate chains and disrupts anterior-posterior and dorsoventral patterning in cells exposed to a midbrain differentiation protocol. Double-knockout cells fail to acquire midbrain fate and instead adopt caudal and neural crest-like identities, as revealed by single-nucleus RNA sequencing. Mechanistically, we find enhanced FGF signaling and demonstrate that FGF inhibition redirects cells toward midbrain progenitors, without fully restoring ventral identity. These findings establish a critical role for SULF1/2 in human mDA neuron development and uncover a previously unrecognized layer of extracellular control over neuronal patterning, opening for novel strategies to refine differentiation protocols for PD and beyond.

2026-07-16 | PXD075443 | Pride

Transcriptional control of Sulf1 by WT1 primes epicardial signalling and fate by modifying extracellular heparan sulfate status [CUT&Run]

Project description:Considering the transcriptional correlations we observed between WT1 and 6-O-endosulfatases in the epicardium, we sought to elucidate whether WT1 regulates 6-O-endosulfatase expression directly and how its binding may differ between Sulf1 and Sulf2 in the epicardium. We employed CUT&RUN-seq experiments that mapped genome-wide binding sites of WT1 and histone modifications in cultured epicardial cells (MEC1). We identified weak, although variable, binding of WT1 to the Sulf1 promoter and significant WT1 binding to an intronic enhancer, marked by active chromatin modification H3K27ac, located in intron 1 of the Sulf1 gene. Interestingly, the CUT&RUN-seq experiments also revealed significant binding of WT1 to the third intron of the Sulf2 gene, displaying chromatin accessibility without any histone marks or gene activity.

2026-08-06 | GSE299998 | GEO

TFCP2 is a transcriptional regulator of heparan sulfate assembly and melanoma cell growth

Project description:Heparan sulfate (HS) is a long, linear polysaccharide that is ubiquitously expressed in all animal cells and plays a key role in many cellular processes, including cell signaling and development. Dysregulation of HS assembly has been implicated in pathophysiological conditions, such as tumorigenesis and rare genetic disorders. HS biosynthesis occurs in a non-template driven manner in the endoplasmic reticulum and Golgi through the activity a large group of biosynthetic enzymes. While much is known about its biosynthesis, little is understood about the regulation of HS assembly across diverse tissue types and disease states. To address this gap in knowledge, we recently performed genome-wide CRISPR/Cas9 screens to identify novel regulatory factors of HS biosynthesis. From these screens, we identified the alpha globin transcription factor, TFCP2, as a top hit. To investigate the role of TFCP2 in HS assembly, we targeted TFCP2 expression in human melanoma cells using the CRISPR/Cas9 system. TFCP2 knockout cells exhibited decreased fibroblast growth factor binding to cell surface HS, alterations in HS composition, and slowed cell growth compared to wildtype cells. Additionally, RNA sequencing revealed that TFCP2 regulates expression of multiple enzymes involved in HS assembly, including the secreted endosulfatase, SULF1. Pharmacological targeting of TFCP2 activity similarly reduced growth factor binding and increased SULF1 expression, and knockdown of SULF1 expression in TFCP2 mutant cells restored melanoma cell growth. Overall, these studies identify TFCP2 as a novel transcriptional regulator of HS and highlight HS-protein interactions as a possible target to slow melanoma growth.

2023-05-01 | GSE224599 | GEO

Heparan Sulfation Dependent FGF Signalling Maintains ES Cells Primed for Differentiation in a Heterogeneous State

Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naÃ¯ve ground state. Four groups with three biological replicates and a technical duplicate in each

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