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Title: Characterization and evolutionary origin of novel C<sub>2</sub>H<sub>2</sub> zinc finger protein (ZNF648) required for both erythroid and megakaryocyte differentiation in humans
Authors: Daniel C.J. Ferguson
Juraidah Haji Mokim
Marjolein Meinders
Edmund R.R. Moody
Tom A. Williams
Sarah Cooke
Kongtana Trakarnsanga
Deborah E. Daniels
Ivan Ferrer-Vicens
Deborah Shoemark
Chartsiam Tipgomut
Katherine A. Macinnes
Marieangela C. Wilson
Belinda K. Singleton
Jan Frayne
University of Bristol
Faculty of Medicine, Siriraj Hospital, Mahidol University
Keywords: Medicine
Issue Date: 5-Oct-2020
Citation: Haematologica. Vol.Online ahead of print, (2020)
Abstract: Human ZNF648 is a novel poly C-terminal C2H2 zinc finger protein identified amongst the most dysregulated proteins in erythroid cells differentiated from iPSC. Its nuclear localisation and structure indicate it is likely a DNA-binding protein. Using a combination of ZNF648 overexpression in an iPSC line and primary adult erythroid cells, ZNF648 knockdown in primary adult erythroid cells and megakaryocytes, comparative proteomics and transcriptomics we show that ZNF648 is required for both erythroid and megakaryocyte differentiation. Orthologues of ZNF648 were detected across Mammals, Reptilia, Actinopterygii, in some Aves, Amphibia and Coelacanthiformes suggesting the gene originated in the common ancestor of Osteichthyes (Euteleostomi or bony fish). Conservation of the C-terminal zinc finger domain is higher, with some variation in zinc finger number but a core of at least six zinc fingers conserved across all groups, with the N-terminus recognisably similar within but not between major lineages. This suggests the N-terminus of ZNF648 evolves faster than the C-terminus, however this is not due to exon-shuffling as the entire coding region of ZNF648 is within a single exon. As for other such transcription factors, the N-terminus likely carries out regulatory functions, but showed no sequence similarity to any known domains. The greater functional constraint on the zinc finger domain suggests ZNF648 binds at least some similar regions of DNA in the different organisms. However, divergence of the N-terminal region may enable differential expression, allowing adaptation of function in the different organisms.
ISSN: 15928721
Appears in Collections:Scopus 2020

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