Meiotic and post meiotic chromatin regulation

During meiotic prophase, all chromosomes must find and connect to their partner by means of a specially formed protein complex called the synaptonemal complex. This process requires the action of a specific enzyme by the name of SPO11, that induces DNA double strand breaks. The process that manages the repair of these meiotic breaks then helps in finding the right pairing partner for each chromosome.

In male cells, the heterologous X and Y chromosomes only connect in the small pseudo-autosomal region. A mechanism identified as meiotic sex chromosome inactivation (MSCI) transcriptionally silences the sex chromosomes, leading to formation of the XY body in the periphery of the nucleus. Autosomal chromosome regions that are left unpaired are likewise transcriptionally silenced in both female and male cells during meiotic prophase. This process is called meiotic silencing of unsynapsed chromatin (MSUC). During post-meiotic development, some genes on X and Y are re-expressed, but in the early female embryo, the paternal X is again silenced.

In our lab, we investigate the role of proteins that are involved in the repair of meiotic breaks, and in the transcriptional inactivation of unpaired chromosomes. We would like to find out how the pairing process of chromosomes is linked to meiotic DNA strand break repair, and how regions in chromosomes that do not match (and therefore should not pair) are identified.

We are also interested in the evolutional conservation of MSUC and MSCI, and have studied these processes for example in birds. Additionally, we study possible transgeneration effects of MSUC and MSCI.

Live cell analyses of synaptonemal complex dynamics and chromosome movements in cultured mouse testis tubules and embryonic ovaries.
Enguita-Marruedo A, Van Cappellen WA, Hoogerbrugge JW, Carofiglio F, Wassenaar E, Slotman JA, Houtsmuller A, Baarends WM.
Chromosoma. 2018 Mar 26. doi: 10.1007/s00412-018-0668-7

Repair of exogenous DNA double-strand breaks promotes chromosome synapsis in SPO11-mutant mouse meiocytes, and is altered in the absence of HORMAD1.
Carofiglio F, Sleddens-Linkels E, Wassenaar E, Inagaki A, van Cappellen WA, Grootegoed JA, Toth A, Baarends WM.
DNA Repair (Amst). 2018 Mar;63:25-38.

Round Spermatid Injection Rescues Female Lethality of a Paternally Inherited Xist Deletion in Mouse. Federici F, Magaraki A, Wassenaar E, van Veen-Buurman CJ, van de Werken C, Baart EB, Laven JS, Grootegoed JA, Gribnau J, Baarends WM.
PLoS Genet. 2016 Oct 7;12(10):e1006358.

Genomes of Ellobius species provide insight into the evolutionary dynamics of mammalian sex chromosomes.
Mulugeta E, Wassenaar E, Sleddens-Linkels E, van IJcken WF, Heard E, Grootegoed JA, Just W, Gribnau J, Baarends WM.
Genome Res. 2016 Sep;26(9):1202-10.

SPO11-independent DNA repair foci and their role in meiotic silencing.
Carofiglio F, Inagaki A, de Vries S, Wassenaar E, Schoenmakers S, Vermeulen C, van Cappellen WA, Sleddens-Linkels E, Grootegoed JA, Te Riele HP, de Massy B, Baarends WM.
PLoS Genet. 2013 Jun;9(6):e1003538

Mulugeta Achame E, Wassenaar E, Hoogerbrugge JW, Sleddens-Linkels E, Ooms M, Sun ZW, van IJcken WF, Grootegoed JA, Baarends WM. (2010) The ubiquitin-conjugating enzyme HR6B is required for maintenance of X chromosome silencing in mouse spermatocytes and spermatids.
BMC Genomics . 2010 Jun 10;11:367.

Inagaki, A., Schoenmakers, S. and Baarends, W. M. (2010) DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis.
Epigenetics 5, 255-266.

Schoenmakers, S., Wassenaar, E., Laven, J. S., Grootegoed, J. A. and Baarends, W. M. (2010) Meiotic silencing and fragmentation of the male germline restricted chromosome in zebra finch.
Chromosoma 119, 311-324

Schoenmakers, S., Wassenaar, E., Hoogerbrugge, J. W., Laven, J. S., Grootegoed, J. A. and Baarends, W. M. (2009) Female meiotic sex chromosome inactivation in chicken.
PLoS Genet 5, e1000466.

Schoenmakers, S., Wassenaar, E., van Cappellen, W. A., Derijck, A. A., de Boer, P., Laven, J. S., Grootegoed, J. A. and Baarends, W. M. (2008) Increased frequency of asynapsis and associated meiotic silencing of heterologous chromatin in the presence of irradiation-induced extra DNA double strand breaks.
Developmental Biology 317, 270-281.

Baarends WM, Wassenaar E, Hoogerbrugge JWH, Schoenmakers S, Sun ZW, Grootegoed JA (2007) Increased H2A_T120 phosphorylation and H3_K4 dimethylation on the XY body in Hr6b knockout mouse spermatocytes is associated with derepression of the X chromosome in spermatids
J Cell Sci 120:1841-1851

Liebe B, Petukhova G, Barchi M, Bellani M, Braselmann H, Nakano T, PanditaTK, Jasin M, Fornace A, Meistrich ML, Baarends WM, Schimenti J, de Lange T, Keeney S, Camerini-Otero RD, Scherthan H. (2006)
Mutations that affect meiosis in male mice influence the dynamics of the mid-preleptotene and bouquet stages
Exp Cell Res. Nov 15;312(19):3768-81.

Wesoly J, Agarwal S, Sigurdsson S, Bussen W, Van Komen S, Qin J, van Steeg H, van Benthem J, Wassenaar E, Baarends WM, Ghazvini M, Tafel AA, Heath H, Galjart N, Essers J, Grootegoed JA, Arnheim N, Bezzubova O, Buerstedde JM, Sung P, Kanaar R (2006) Differential contributions of mammalian Rad54 paralogs to recombination, DNA damage repair, and meiosis
Mol Cell Biol Feb;26(3):976-89.

de Vries FA, de Boer E, van den Bosch M, Baarends WM, Ooms M, Yuan L, Liu JG, van Zeeland AA, Heyting C, Pastink A (2005)
Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation
Genes Dev. Jun 1;19(11):1376-89.

Baarends WM, Wassenaar E, van der Laan R, Hoogerbrugge J, Sleddens-Linkels E, Hoeijmakers JH, de Boer P, Grootegoed JA. Silencing of unpaired chromatin and histone H2A ubiquitination in mammalian meiosis (2005)
Mol Cell Biol Feb;25(3):1041-53.

Siep M, Sleddens-Linkels E, Mulders S, van Eenennaam H, Wassenaar E, Van Cappellen WA, Hoogerbrugge J, Grootegoed JA, Baarends WM (2004)
Basic helix-loop-helix transcription factor Tcfl5 interacts with the Calmegin gene promoter in mouse spermatogenesis
Nucleic Acids Res Dec 7;32(21):6425-36.

van der Laan R, Uringa EJ, Wassenaar E, Hoogerbrugge JW, Sleddens E, Odijk H, Roest HP, de Boer P, Hoeijmakers JH, Grootegoed JA, Baarends WM (2004)
Ubiquitin ligase Rad18Sc localizes to the XY body and to other chromosomal regions that are unpaired and transcriptionally silenced during male meiotic prophase
J Cell Sci. Oct 1;117(Pt 21):5023-33.

Baarends WM, Wassenaar E, Hoogerbrugge JW, van Cappellen G, Roest HP, Vreeburg J, Ooms M, Hoeijmakers JH, Grootegoed JA (2003)
Loss of HR6B ubiquitin-conjugating activity results in damaged synaptonemal complex structure and increased crossing-over frequency during the male meiotic prophase
Mol Cell Biol. Feb;23(4):1

Group leader: Willy Baarends

Group members: Esther Sleddens-Linkels, Lieke Koornneef, Kaylee Holleman, Aditya Mhaskar, Arina Puchkina, Ilse de Bruin