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Disrupting the DREAM transcriptional repressor complex induces apolipoprotein overexpression and systemic amyloidosis in mice
Pirunthan Perampalam, … , Vathany Kulasingam, Frederick A. Dick
Pirunthan Perampalam, … , Vathany Kulasingam, Frederick A. Dick
Published January 14, 2021
Citation Information: J Clin Invest. 2021;131(4):e140903. https://doi.org/10.1172/JCI140903.
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Research Article Nephrology Vascular biology Article has an altmetric score of 2

Disrupting the DREAM transcriptional repressor complex induces apolipoprotein overexpression and systemic amyloidosis in mice

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Abstract

DREAM (Dp, Rb-like, E2F, and MuvB) is a transcriptional repressor complex that regulates cell proliferation, and its loss causes neonatal lethality in mice. To investigate DREAM function in adult mice, we used an assembly-defective p107 protein and conditional deletion of its redundant family member p130. In the absence of DREAM assembly, mice displayed shortened survival characterized by systemic amyloidosis but no evidence of excessive cellular proliferation. Amyloid deposits were found in the heart, liver, spleen, and kidneys but not the brain or bone marrow. Using laser-capture microdissection followed by mass spectrometry, we identified apolipoproteins as the most abundant components of amyloids. Intriguingly, apoA-IV was the most detected amyloidogenic protein in amyloid deposits, suggesting apoA-IV amyloidosis (AApoAIV). AApoAIV is a recently described form, whereby WT apoA-IV has been shown to predominate in amyloid plaques. We determined by ChIP that DREAM directly regulated Apoa4 and that the histone variant H2AZ was reduced from the Apoa4 gene body in DREAM’s absence, leading to overexpression. Collectively, we describe a mechanism by which epigenetic misregulation causes apolipoprotein overexpression and amyloidosis, potentially explaining the origins of nongenetic amyloid subtypes.

Authors

Pirunthan Perampalam, Haider M. Hassan, Grace E. Lilly, Daniel T. Passos, Joseph Torchia, Patti K. Kiser, Andrea Bozovic, Vathany Kulasingam, Frederick A. Dick

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Figure 5

ApoA-IV is the most abundant amyloidogenic protein in p107D/D p130–/– amyloid deposits.

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ApoA-IV is the most abundant amyloidogenic protein in p107D/D p130–/– am...
(A) H&E staining of kidney from an endpoint p107D/D p130–/– mouse. Arrows indicate acellular eosinophilic material. Scale bar: 50 μm. (B) Congo red staining of a serial section of the same kidney as in A. Black arrows indicate the same acellular material under bright-field optics as in A. White arrows mark the same locations under polarized and fluorescent optics. Scale bars: 50 μm. (C) Schematic illustration of LMD/MS procedure: Congo red–positive regions were laser captured and processed for mass spectrometry to identify peptides present in amyloids. (D) Per spectral match quantities were scaled relative to the most abundant protein in each sample, apoE. Rows (proteins) were clustered and values are represented as indicated by the scale at the bottom. Each column represents an organ from an endpoint p107D/D p130–/– mouse. (E–G) Total RNA was used to synthesize cDNA. Gene expression was determined by qPCR in 3-month-old, 1-year-old, and endpoint p107D/D p130fl/fl and p107D/D p130–/– mice and normalized to Gapdh for each age group (n = 4). Bar graphs show mean expression values for Apoa1 (E), Apoa2 (F), Apoa4 (G) and error bars represent 1 standard deviation. Values are normalized to that of p107D/D p130fl/fl at each age for each gene. Two-way ANOVA was performed for each gene and significance levels are indicated (****P < 0.0001; NS, P > 0.05). (H) Protein extracts from the livers of 3-month-old p107D/D p130fl/fl and p107D/D p130–/– mice were Western blotted for the indicated proteins. Numerical values represent band intensity ratio of apoA-IV relative to vinculin.

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