14 / 2024-08-28 05:35:06

Dynamics of extreme long Polycomb loops in cancer.

leukemia,cancer

Chromosomal loops are CTCF-cohesion mediated 3D genomic structure in mammalian nucleus. Besides the CTCF-cohesion loops, other epigenomic marks could also form long-range interactions in the nucleus. Polycomb targeted loci, which is regulated through Polycomb repressive complex and trithorax complex during development, form long-range chromatin interactions independent of CTCF-cohesion and demarcated by low DNA methylation. We found such extremely long Polycomb loops (XL-Polycomb loops) could occur between loci separated by up to 60 Mbs, and exclusively in cells of self-renewal status like human hematopoietic stem cells and mouse embryonic stem cells. Due to the interactions’ association with self-renewal status of cells, we tested if XL-Polycomb loops could been observed and played a role in cancer. We therefore profiled 7 primary acute myeloid leukemia (AML) blast and 3 AML cell lines. To our surprise, we found in most of primary AMLs a significant loss of XL-Polycomb loops, and such loss is exacerbated in AML cell lines. Accompanied with loss of XL-Polycomb loops, DNA hypermethylation and loss of Polycomb binding is observed at the anchor loci of XL-Polycomb loops in primary AML samples and further exacerbated in cell line. Interestingly, these silenced loci (most of them are mesoderm transcriptional factors) switched to activated chromatin status in the AML samples and forms de novo 3D genomic interaction anchor sites in AMLs.

Surprisingly, in one specific AML which is of more stem cell subtype, AML-specific XL-Polycomb loops are particularly strong despite the DNA hypermethylation and loss of Polycomb mark. We found that AML is sensitive to EZH2 inhibition. EZH2 inhibition also caused differentiation of this AML and activated neutrophil-associated differentiation transcriptional program. This case suggests certain cancer may display strong XL-Polycomb loops interactions, which plays a role in the cancer development and renders the sensitivity to Polycomb disruption.

Chromosomal loops are CTCF-cohesion mediated 3D genomic structure in mammalian nucleus. Besides the CTCF-cohesion loops, other epigenomic marks could also form long-range interactions in the nucleus. Polycomb targeted loci, which is regulated through Polycomb repressive complex and trithorax complex during development, form long-range chromatin interactions independent of CTCF-cohesion and demarcated by low DNA methylation. We found such extremely long Polycomb loops (XL-Polycomb loops) could occur between loci separated by up to 60 Mbs, and exclusively in cells of self-renewal status like human hematopoietic stem cells and mouse embryonic stem cells. Due to the interactions’ association with self-renewal status of cells, we tested if XL-Polycomb loops could been observed and played a role in cancer. We therefore profiled 7 primary acute myeloid leukemia (AML) blast and 3 AML cell lines. To our surprise, we found in most of primary AMLs a significant loss of XL-Polycomb loops, and such loss is exacerbated in AML cell lines. Accompanied with loss of XL-Polycomb loops, DNA hypermethylation and loss of Polycomb binding is observed at the anchor loci of XL-Polycomb loops in primary AML samples and further exacerbated in cell line. Interestingly, these silenced loci (most of them are mesoderm transcriptional factors) switched to activated chromatin status in the AML samples and forms de novo 3D genomic interaction anchor sites in AMLs.

Surprisingly, in one specific AML which is of more stem cell subtype, AML-specific XL-Polycomb loops are particularly strong despite the DNA hypermethylation and loss of Polycomb mark. We found that AML is sensitive to EZH2 inhibition. EZH2 inhibition also caused differentiation of this AML and activated neutrophil-associated differentiation transcriptional program. This case suggests certain cancer may display strong XL-Polycomb loops interactions, which plays a role in the cancer development and renders the sensitivity to Polycomb disruption.