scholarly journals ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ankur Gadgil ◽  
Agnieszka Walczak ◽  
Agata Stępień ◽  
Jonas Mechtersheimer ◽  
Agnes Lumi Nishimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Histone Gene ◽  
Cytoplasmic Inclusions ◽  
Cellular Models ◽  
Histone Gene Expression ◽  
Genes Encoding ◽  
U7 Snrnp ◽  
Processing Event ◽  
Fus Protein

AbstractGenes encoding replication-dependent histones lack introns, and the mRNAs produced are a unique class of RNA polymerase II transcripts in eukaryotic cells that do not end in a polyadenylated tail. Mature mRNAs are thus formed by a single endonucleolytic cleavage that releases the pre-mRNA from the DNA and is the only processing event necessary. U7 snRNP is one of the key factors that determines the cleavage site within the 3ʹUTR of replication-dependent histone pre-mRNAs. We have previously showed that the FUS protein interacts with U7 snRNA/snRNP and regulates the expression of histone genes by stimulating transcription and 3ʹ end maturation. Mutations in the FUS gene first identified in patients with amyotrophic lateral sclerosis (ALS) lead to the accumulation of the FUS protein in cytoplasmic inclusions. Here, we report that mutations in FUS lead to disruption of the transcriptional activity of FUS and mislocalization of U7 snRNA/snRNP in cytoplasmic aggregates in cellular models and primary neurons. As a consequence, decreased transcriptional efficiency and aberrant 3ʹ end processing of histone pre-mRNAs were observed. This study highlights for the first time the deregulation of replication-dependent histone gene expression and its involvement in ALS.

scholarly journals Replication-dependent Histone Gene Expression Is Related to Cajal Body (CB) Association but Does Not Require Sustained CB Contact

2001 ◽  
Vol 12 (3) ◽  
pp. 565-576 ◽  
Author(s):  
Lindsay S. Shopland ◽  
Meg Byron ◽  
Janet L. Stein ◽  
Jane B. Lian ◽  
Gary S. Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Histone Gene ◽  
Cajal Body ◽  
Histone Gene Expression ◽  
U7 Snrnp ◽  
A Cell ◽  
First Time ◽  
Encoding Genes ◽  
Modest Correlation

Interactions between Cajal bodies (CBs) and replication-dependent histone loci occur more frequently than for other mRNA-encoding genes, but such interactions are not seen with all alleles at a given time. Because CBs contain factors required for transcriptional regulation and 3′ end processing of nonpolyadenylated replication-dependent histone transcripts, we investigated whether interaction with CBs is related to metabolism of these transcripts, known to vary during the cell cycle. Our experiments revealed that a locus containing a cell cycle-independent, replacement histone gene that produces polyadenylated transcripts does not preferentially associate with CBs. Furthermore, modest but significant changes in association levels of CBs with replication-dependent histone loci mimic their cell cycle modulations in transcription and 3′ end processing rates. By simultaneously visualizing replication-dependent histone genes and their nuclear transcripts for the first time, we surprisingly find that the vast majority of loci producing detectable RNA foci do not contact CBs. These studies suggest some link between CB association and unusual features of replication-dependent histone gene expression. However, sustained CB contact is not a requirement for their expression, consistent with our observations of U7 snRNP distributions. The modest correlation to gene expression instead may reflect transient gene signaling or the nucleation of small CBs at gene loci.

scholarly journals Super resolution light microscopy of the Drosophila Histone Locus Body reveals a core-shell organization associated with expression of replication dependent histone genes

2021 ◽  
pp. mbc.E20-10-0645
Author(s):  
James P. Kemp ◽  
Xiao-Cui Yang ◽  
Zbigniew Dominski ◽  
William F. Marzluff ◽  
Robert J. Duronio
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Nuclear Body ◽  
Histone Gene ◽  
Core Shell ◽  
Histone Genes ◽  
The Core ◽  
Histone Gene Expression ◽  
Histone Locus ◽  
Histone Gene Transcription

The Histone Locus Body (HLB) is an evolutionarily conserved nuclear body that regulates the transcription and processing of replication-dependent (RD) histone mRNAs, which are the only eukaryotic mRNAs lacking a poly-A tail. Many nuclear bodies contain distinct domains, but how internal organization is related to nuclear body function is not fully understood. Here, we demonstrate using structured illumination microscopy that Drosophila HLBs have a “core-shell” organization in which the internal core contains transcriptionally active RD histone genes. The N-terminus of Mxc, which contains a domain required for Mxc oligomerization, HLB assembly, and RD histone gene expression, is enriched in the HLB core. In contrast, the C-terminus of Mxc is enriched in the HLB outer shell as is FLASH, a component of the active U7 snRNP that co-transcriptionally cleaves RD histone pre-mRNA. Consistent with these results, we show biochemically that FLASH binds directly to the Mxc C-terminal region. In the rapid S-M nuclear cycles of syncytial blastoderm Drosophila embryos, the HLB disassembles at mitosis and reassembles the core-shell arrangement as histone gene transcription is activated immediately after mitosis. Thus, the core-shell organization is coupled to zygotic histone gene transcription, revealing a link between HLB internal organization and RD histone gene expression.

scholarly journals Positive cofactor 4 (PC4) contributes to the regulation of replication-dependent canonical histone gene expression

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Aleksandra Brzek ◽  
Marlena Cichocka ◽  
Jakub Dolata ◽  
Wojciech Juzwa ◽  
Daniel Schümperli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Gene ◽  
Histone Gene Expression ◽  
Canonical Histone
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