Mapping chromatin compartments remodeling in cancer by their biochemical properties

The three-dimensional (3D) organization of chromatin within the cell nucleus governs the spatial segregation
of euchromatin and heterochromatin into active and inactive compartments. As spatially confined chromatin
domains share similar epigenetic features and biochemical properties, in terms of accessibility and solubility,
these properties can be exploited to reconstruct genome compartmentalization. On this rationale we
developed 4f-SAMMY-seq, an epigenomic technique to map open and closed chromatin domains and,
through a tailored bioinformatic approach, recapitulate their 3D segregation into compartments and sub-
compartments within a single experiment. A key strength of the method is its applicability to small, fresh
tissue samples, making it uniquely suited to the study of clinical specimens.
We applied this approach to investigate chromatin compartment remodeling in primary prostate cancer
patients biopsies. Genome-wide mapping of chromatin compartments in chemo-naïve patient biopsies,
complemented by parallel transcriptome analysis, revealed two subgroups defined by the degree of
chromatin 3D architecture alteration: a Low (LDD) and a High (HDD) Degree of Decompartmentalization.
The HDD subtype was associated with extensive compartment remodeling and transcriptional repression,
indicative of a protective, antitumoral state. From these alterations we derived a transcriptional signature
whose prognostic relevance was confirmed across multiple cohorts totaling more than 900 patients. Overall,
we found that profiling chromatin compartments by their biochemical properties provides a novel prognostic
tool applicable at the time of diagnostic biopsy.