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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 3

Systemic amyloidosis in p107D/D p130–/– mice.

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Systemic amyloidosis in p107D/D p130–/– mice.
(A–D) Tissue sections of h...
(A–D) Tissue sections of heart (A), kidney (B), liver (C), and spleen (D) from endpoint p107D/D p130–/– mice were stained with Congo red. Bright field images were captured along with corresponding apple green birefringence under polarized light. Scale bars: 20 μm. (E) FFPE tissues were processed for TEM. Ultrastructure of acellular material in the kidney is shown. Black arrows indicate fibril structure in this organ. Scale bars: 2 μm and 1 μm (enlarged inset). (F) Fibril diameters in kidney TEM images were measured. Bar graph represents mean diameter obtained from individual fibril measurements, and error bars indicate 1 SD (n = 9). (G–H) TEM images of FFPE heart (G) and liver (H) tissue. Black arrows indicate areas of fibril deposition. For orientation, the asterisk indicates mitochondria in cardiomyocytes, and the pound sign denotes red blood cells in a hepatic capillary.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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