Making fundamental scientific discoveries by combining information from literature, databases, and computational tools – An example

Stielow, Bastian; Simon, Clara; Liefke, Robert

doi:10.1016/j.csbj.2021.04.052

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Consequently, the absence of SAMD1 typically leads to the derepression of its target genes 4 , 9 . SAMD1 is often upregulated in cancer tissues and correlates with worse prognosis in some cancer types, such as adenoid cystic carcinoma (ACC) and liver cancer 9 , 13 . A CRISPR screen in K562 cells suggested that SAMD1 is required for the efficient proliferation of these cells 14 .…”

Section: Introductionmentioning

confidence: 99%

Investigation of SAMD1 ablation in mice

Campbell¹,

Weber

Engle

et al. 2023

Sci Rep

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SAM domain-containing protein 1 (SAMD1) has been implicated in atherosclerosis, as well as in chromatin and transcriptional regulation, suggesting a versatile and complex biological function. However, its role at an organismal level is currently unknown. Here, we generated SAMD1−/− and SAMD1+/− mice to explore the role of SAMD1 during mouse embryogenesis. Homozygous loss of SAMD1 was embryonic lethal, with no living animals seen after embryonic day 18.5. At embryonic day 14.5, organs were degrading and/or incompletely developed, and no functional blood vessels were observed, suggesting failed blood vessel maturation. Sparse red blood cells were scattered and pooled, primarily near the embryo surface. Some embryos had malformed heads and brains at embryonic day 15.5. In vitro, SAMD1 absence impaired neuronal differentiation processes. Heterozygous SAMD1 knockout mice underwent normal embryogenesis and were born alive. Postnatal genotyping showed a reduced ability of these mice to thrive, possibly due to altered steroidogenesis. In summary, the characterization of SAMD1 knockout mice suggests a critical role of SAMD1 during developmental processes in multiple organs and tissues.

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Section: Introductionmentioning

confidence: 99%

Investigation of SAMD1 ablation in mice

Campbell¹,

Weber

Engle

et al. 2023

Sci Rep

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“…On the other hand, KDM2B and mammalian Polycomb-like proteins are associated with Polycomb repressive complexes and are involved in gene repression ( 33–35 ). Recently, we identified the SAM domain-containing protein 1 (SAMD1) as another protein that specifically binds to unmethylated CpG motifs ( 36 , 37 ). SAMD1 is associated with L3MBTL3 and the KDM1A histone demethylase complex and functions as a transcriptional repressor ( 36 , 38 ).…”

Section: Introductionmentioning

confidence: 99%

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain

Weber

Jia

Stielow

et al. 2022

Nucleic Acids Research

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The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.

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“…SAMD1 has homology across primates, canines, rodents, and rabbits, and orthology with at least 250 organisms, and SAMD1 RNA is found in numerous organs and tissues in humans and mice [1], [2], [3]; the extensiveness of expression suggests roles in adult homeostasis. SAMD1 was minimally studied until very recently [4]. A 2021 report supports SAMD1's participation in LDL retention and uptake, finding that SAMD1 knockdown suppresses Vascular Smooth Muscle Cell (VSMC) differentiation and proliferation, and that SAMD1/LDL binding on VSMCs leads to LDL oxidation and foam cell development [5].…”

Section: Introductionmentioning

confidence: 99%

Ablation of SAMD1 in Mice Causes Failure of Angiogenesis, Embryonic Lethality

Campbell

Engle

Bourassa

et al. 2022

Preprint

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Pathological retention of LDL in the intima is involved in atherosclerosis, although the retention mechanisms are not well-understood. Previously, we reported Sterile Alpha Motif Domain Containing 1 (SAMD1), a protein secreted by intimal smooth muscle cells in atherosclerotic lesions, appears to bind LDL in extracellular matrix around intimal cells. Fab-fragment inhibitors of apparently irreversible SAMD1/LDL binding reduced LDL retention in carotid injury models, but did not have a significant effect on early spontaneous lesion initiation. The normal function of SAMD1 is unknown, but it may have multiple epigenetic roles; our histology of mouse atherosclerosis models revealed extensive SAMD1 expression, possibly related to cell phenotype modulation and antigen presentation. For this report, we generated SAMD1-/-, SAMD1-/+, and SAMD1-/+ apoE-/- mice to further explore SAMD1's role in atherosclerosis. SAMD1 was found in tissues throughout the SAMD1+/+ and SAMD1-/+embryos. Homozygous loss of SAMD1 was embryonic lethal: at embryonic day 14, organs were partially developed and/or degraded; heads and brains were malformed; no blood vessels were observed; red blood cells were scattered and pooled, primarily near the embryo surface; and cell death was occurring. Development appeared normal in heterozygous SAMD1 embryos, but postnatal genotyping showed a reduced ability to thrive. Growth of atherosclerotic lesions in SAMD1-/+ apoE-/- after 35 weeks was not significantly less than in mice SAMD1+/+ apoE-/- mice.

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Making fundamental scientific discoveries by combining information from literature, databases, and computational tools – An example

Cited by 10 publications

References 44 publications

Investigation of SAMD1 ablation in mice

Investigation of SAMD1 ablation in mice

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain

Ablation of SAMD1 in Mice Causes Failure of Angiogenesis, Embryonic Lethality

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