4.6 Article

Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

Journal

CARCINOGENESIS
Volume 39, Issue 6, Pages 788-797

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgy056

Keywords

-

Categories

Funding

  1. Jane and Aatos Erkko Foundation
  2. Helsinki Institute of Life Science

Ask authors/readers for more resources

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1(+/-)) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

Editorial Material Cell & Tissue Engineering

The Continued Absence of Functional Germline Stem Cells in Adult Ovaries

Masahito Yoshihara, Magdalena Wagner, Anastasios Damdimopoulos, Cheng Zhao, Sophie Petropoulos, Shintaro Katayama, Juha Kere, Fredrik Lanner, Pauliina Damdimopoulou

Summary: Ovaries play a crucial role in the development, fertility, and reproduction of women. They age faster than other tissues and their function is lost before other organs undergo senescence. While there have been debates about the presence of germline stem cells and neo-oogenesis in adult human ovaries, our recent analysis did not find evidence of such stem cells. However, we welcome discussions on different protocols and acknowledge the importance of excellence in methods.

STEM CELLS (2023)

Article Immunology

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Elina A. Tuovinen, Outi Kuismin, Leila Soikkonen, Timi Martelius, Meri Kaustio, Sari Hamalainen, Hanna Viskari, Jaana Syrjanen, Ulla Wartiovaara-Kautto, Kari K. Eklund, Janna Saarela, Markku Varjosalo, Juha Kere, Timo Hautala, Mikko R. J. Seppanen

Summary: The NF-κB family of transcription factors is important in cellular signaling pathways, and NFKB1 variants have been associated with CVID and immunodeficiency. However, the penetrance and prevalence of CVID are relatively low, while inflammatory manifestations are more common.

CLINICAL IMMUNOLOGY (2023)

Letter Cell & Tissue Engineering

Reply: Revisiting Claims of the Continued Absence of Functional Germline Stem Cells in Adult Ovaries

Masahito Yoshihara, Magdalena Wagner, Anastasios Damdimopoulos, Cheng Zhao, Sophie Petropoulos, Shintaro Katayama, Juha Kere, Fredrik Lanner, Pauliina Damdimopoulou

STEM CELLS (2023)

Article Multidisciplinary Sciences

B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors

Daniel F. Kaemena, Masahito Yoshihara, Meryam Beniazza, James Ashmore, Suling Zhao, Marten Bertenstam, Victor Olariu, Shintaro Katayama, Keisuke Okita, Simon R. Tomlinson, Kosuke Yusa, Keisuke Kaji

Summary: CRISPR/Cas9-mediated genome-wide knockout screening identified 24 reprogramming roadblock genes, among which depletion of the predicted KRAB zinc finger protein Zfp266 consistently enhanced murine iPSC generation in various reprogramming settings. ZFP266 was found to bind to Short Interspersed Nuclear Elements (SINEs) near the binding sites of OCT4, SOX2, and KLF4, inhibiting chromatin opening. Replacement of the KRAB co-suppressor with co-activator domains transformed ZFP266 from an inhibitor to a potent facilitator of iPSC reprogramming. The interaction between SINE and KRAB-ZFP is proposed to be a critical regulator of chromatin accessibility for efficient cellular identity changes.

NATURE COMMUNICATIONS (2023)

Article Cardiac & Cardiovascular Systems

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

Jaakko S. Tyrmi, Tea Kaartokallio, A. Inkeri Lokki, Tiina Jaaskelainen, Eija Kortelainen, Sanni Ruotsalainen, Juha Karjalainen, Samuli Ripatti, Anna Kivioja, Triin Laisk, Johannes Kettunen, Anneli Pouta, Katja Kivinen, Eero Kajantie, Seppo Heinonen, Juha Kere, Hannele Laivuori

Summary: This study used a genome-wide association study to uncover the genetic factors underlying preeclampsia and maternal hypertension during pregnancy. The analysis identified several novel genetic associations and found that genes related to blood pressure traits are also associated with preeclampsia. These findings suggest a connection between cardiovascular function and the development of preeclampsia.

JAMA CARDIOLOGY (2023)

Article Multidisciplinary Sciences

Comprehensive characterization of the embryonic factor LEUTX

Lisa Gawriyski, Eeva-Mari Jouhilahti, Masahito Yoshihara, Liangru Fei, Jere Weltner, Tomi T. Airenne, Ras Trokovic, Shruti Bhagat, Mari H. Tervaniemi, Yasuhiro Murakawa, Kari Salokas, Xiaonan Liu, Sini Miettinen, Thomas R. Burglin, Biswajyoti Sahu, Timo Otonkoski, Mark S. Johnson, Shintaro Katayama, Markku Varjosalo, Juha Kere

Summary: LEUTX, a transcription factor, is expressed in human preimplantation embryos at the 4-8 cell stages and silenced in somatic tissues. Through multiomic characterization, we found that LEUTX interacts with histone acetyltransferases, EP300 and CBP, via its 9 amino acid transactivation domain. It targets genomic cis-regulatory sequences overlapping with repetitive elements and functions as a transcriptional activator, upregulating genes involved in preimplantation development and 8-cell-like markers.

ISCIENCE (2023)

Article Cell Biology

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Andrea Bieder, Gayathri Chandrasekar, Arpit Wason, Steffen Erkelenz, Jay Gopalakrishnan, Juha Kere, Isabel Tapia-Paez

Summary: This study discovered the physical protein-protein interaction between DYX1C1 and DCDC2 genes, as well as their interactions with the centrosomal protein CPAP. It also found a synergistic genetic interaction between dyx1c1 and dcdc2b in zebrafish, exacerbating the ciliary phenotype. Furthermore, a mutual effect on transcriptional regulation was observed between DYX1C1 and DCDC2 in a cellular model.

BMC MOLECULAR AND CELL BIOLOGY (2023)

Article Genetics & Heredity

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Julia E. Niskanen, Asa Ohlsson, Ingrid Ljungvall, Michaela Droegemueller, Robert F. Ernst, Dennis Dooijes, Hanneke W. M. van Deutekom, J. Peter van Tintelen, Christian J. B. Snijders Blok, Marion van Vugt, Jessica van Setten, Folkert W. Asselbergs, Aleksandra Domanjko Petric, Milla Salonen, Sruthi Hundi, Matthias Hoertenhuber, DoGA Consortium, Juha Kere, W. Glen Pyle, Jonas Donner, Alex V. Postma, Tosso Leeb, Goran Andersson, Marjo K. Hytonen, Jens Haggstrom, Maria Wiberg, Jana Friederich, Jenny Eberhard, Magdalena Harakalova, Frank G. van Steenbeek, Gerhard Wess, Hannes Lohi

Summary: This study used a canine model of dilated cardiomyopathy (DCM) to perform genome-wide analysis and identified two novel candidate genes associated with DCM. It also revealed the complex genetic factors involved in the disease, including cardiac function, energy homeostasis, and morphology. Additionally, the study found candidate variants in these two genes in human DCM patients.

GENOME MEDICINE (2023)

Article Cell & Tissue Engineering

Transcriptomic differences between human 8-cell-like cells reprogrammed with different methods

Masahito Yoshihara, Juha Kere

Summary: This study summarizes the methods of classifying and analyzing a type of cells in human embryos using single-cell RNA sequencing technology, which will facilitate further research on gene activation and early development in human embryos.

STEM CELL REPORTS (2023)

Article Biochemical Research Methods

Optimized single-cell RNA sequencing protocol to study early genome activation in mammalian preimplantation development

Nina Boskovic, Gamze Yazgeldi, Sini Ezer, Mari H. Tervaniemi, Jose Inzunza, Spyridon Panagiotis Deligiannis, Baris Yasar, Tiina Skoog, Kaarel Krjutskov, Shintaro Katayama, Juha Kere

Summary: This article presents a modified single-cell tagged reverse transcription protocol for studying gene expression at the single-cell level or with limited RNA input. The authors describe various enzymes, a modified lysis buffer, and additional clean-up steps before cDNA amplification. They also provide an optimized single-cell RNA sequencing method for studying mammalian preimplantation development using handpicked single cells or tens to hundreds of cells as input material. For complete details on the use and execution of this protocol, please refer to Ezer et al.1.

STAR PROTOCOLS (2023)

Article Cell Biology

Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes

Anniina Pirttiniemi, Krishna Adeshara, Natalie Happonen, Elisabet Einarsdottir, Shintaro Katayama, Hanne Salmenkari, Sohvi Horkko, Juha Kere, Per-Henrik Groop, Markku Lehto

Summary: Inorganic polyphosphates are bioactive phosphate polymers found in all living organisms, and in mammals, they play a vital role in regulating cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates, particularly P700, can modulate the type I interferon signaling and cytokine secretion in human leukocytes. P700 treatment decreases interferon signaling and subsequent gene expression, while augmenting the secretion of various cytokines. This study demonstrates the extensive modulatory effects of P700 on cytokine signaling, specifically targeting type I interferon signaling in human leukocytes.

JOURNAL OF LEUKOCYTE BIOLOGY (2023)

Meeting Abstract Biochemistry & Molecular Biology

Experimental validation of PRD-like homeobox genes expressed in bovine oocytes and early IVF embryos

Baris Yasar, Nina Boskovic, Eeva-Mari Jouhilahti, Piibe Vill, Thomas Burglin, Shintaro Katayama, Tonis Org, Juha Kere, Ants Kurg

EUROPEAN JOURNAL OF HUMAN GENETICS (2023)

No Data Available