ZFP57 plays a role in the maintenance of parent-of-origin-dependent epigenetic state of the Imprinting Control Regions (ICRs) that regulate hundreds of imprinted loci. We report co-occupancy of ZFP57 and associated chromatin modifiers-KAP1, Hp1g and H3K9me3 in the genome of murine embrional stem cells (ESCs) , showing that seemingly it occurs at regions enriched of certain variants of the ZFP57 binding site (BS). The majority of ZFP57 bound regions reside at non-ICRs, notably at additional germ-line DNA methylated CpG islands (CGIs) and certain repeats, implying a wider role for this factor in the shaping of the epigenome. These regions and cognate BSs display a higher DNA methylation compared to the genome of pluripotent ES cells either grown in two kinase inhibitor (2i) or serum+LIF, conditions known to differentially affect their interconvertible DNA methylomes. Non-ICR bound regions in ES cells grown in serum+LIF, have a higher state of methylation in naive ES cells grown in 2i, while ICRs appear stable. We show that the factor selects DNA methylated alleles both at monoallelic marked ICRs and at additional targets. This indicates that the in vivo epigenetic state of potential targets might be a selective factor for stable association along with certain BS variants, density and arrangement, in a context dependent manner. While highly expressed in ES cells and down-regulated upon their differentiation, ZFP57 is expressed in the developing embryo at several sites, notably in the nervous system. We show that it binds to ICRs at different developmental stages. Upon in vitro neural differentiation of ES cells, ZFP57 KO cells show differentiation defects and pertubation of the Notch signaling pathway. The data support the notion that the dynamics of DNA methylation and the regulated expression of the factor shape a wider role than the maintenance of parental allelic asymmetry at ICRs during early embryo epigenetic reprogramming
Dynamics of the imprinting maintenance ZFP57/KAP1 and associated factors network at DNA methylated targets in pluripotent ES cells and insights into a potential developmental/differentiation role
I De Feis;S Filosa;A Fico;G Bellenchi;A Simeone;A Riccio;C Angelini;G Grimaldi
2015
Abstract
ZFP57 plays a role in the maintenance of parent-of-origin-dependent epigenetic state of the Imprinting Control Regions (ICRs) that regulate hundreds of imprinted loci. We report co-occupancy of ZFP57 and associated chromatin modifiers-KAP1, Hp1g and H3K9me3 in the genome of murine embrional stem cells (ESCs) , showing that seemingly it occurs at regions enriched of certain variants of the ZFP57 binding site (BS). The majority of ZFP57 bound regions reside at non-ICRs, notably at additional germ-line DNA methylated CpG islands (CGIs) and certain repeats, implying a wider role for this factor in the shaping of the epigenome. These regions and cognate BSs display a higher DNA methylation compared to the genome of pluripotent ES cells either grown in two kinase inhibitor (2i) or serum+LIF, conditions known to differentially affect their interconvertible DNA methylomes. Non-ICR bound regions in ES cells grown in serum+LIF, have a higher state of methylation in naive ES cells grown in 2i, while ICRs appear stable. We show that the factor selects DNA methylated alleles both at monoallelic marked ICRs and at additional targets. This indicates that the in vivo epigenetic state of potential targets might be a selective factor for stable association along with certain BS variants, density and arrangement, in a context dependent manner. While highly expressed in ES cells and down-regulated upon their differentiation, ZFP57 is expressed in the developing embryo at several sites, notably in the nervous system. We show that it binds to ICRs at different developmental stages. Upon in vitro neural differentiation of ES cells, ZFP57 KO cells show differentiation defects and pertubation of the Notch signaling pathway. The data support the notion that the dynamics of DNA methylation and the regulated expression of the factor shape a wider role than the maintenance of parental allelic asymmetry at ICRs during early embryo epigenetic reprogrammingI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
