Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive.Here we have identified meiosis-specific kinetochore factor MEIKIN in mouse, which functions in meiosis I but neither in meiosis II nor in mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated largely by the activity of Polo-like kinase PLK1, which is enriched to kinetochores depending on MEIKIN. Our integrative analysis indicates that MEIKIN is the long awaited key regulator of meiotic kinetochore function, which is conserved from yeasts to humans. 2In mitosis, sister chromatid cohesion is established depending on cohesin in S phase and maintained until metaphase when the sister chromatids are captured by spindle microtubules from opposite poles and aligned on the spindle equator. For the onset of anaphase, the anaphase-promoting complex (APC) triggers the degradation of securin, an inhibitory chaperone for separase that cleaves cohesin RAD21 and removes cohesin along the entire chromosome. This removal of cohesin triggers the separation of sister chromatids and their movement to opposite poles, a process called equational division [1][2][3] . During meiosis, however, meiotic cohesin REC8 largely replaces RAD21 along the entire chromosomes; one round of DNA replication is followed by two rounds of nuclear division, which results in four haploid nuclei or gametes (Fig. 1a).In the first division of meiosis (meiosis I), homologous chromosomes connected by chiasmata are captured from the opposite poles, while sisters are captured from the same pole (mono-orientation). At the onset of anaphase I, REC8 cohesin is cleaved by separase along the arm regions, but protected at centromeres until metaphase II 4-6 . Thus, mono-orientation and centromeric cohesion protection are two hallmarks of meiotic kinetochore function, which are widely conserved among eukaryotic organisms 7-9 (Fig. 1a). There is accumulating evidence that cohesion protection is mediated by the centromeric protein shugoshin (SGO) and its partner protein phosphatase 2A (PP2A) [10][11][12][13][14][15] , which antagonizes REC8 phosphorylation, a prerequisite of cleavage 16, 17 . So far, meiosis-specific kinetochore proteins have been identified only in two yeasts (S. cerevisiae Spo13 and Mam1 (monopolin subunit), and S. pombe Moa1) [18][19][20][21][22][23] . Puzzlingly, however, because their structural and functional similarities remain to be identified, conservation of meiotic kinetochore regulation is questionable even between yeasts 8, 9 . Therefore, in this study, we address the long-standing question of whether meiotic kinetochore regulation is conserved from yeasts to mammals, and, if so, how. Mammalian meiotic kinetochore protein MEIKINFission yeast Moa1 interacts directly with the conserved kinetochore protein Cnp3 (CENP-C homolog), and localizes to the kinetochore in meiosis I 24 . To identify an equivalent meiosis...

Highlights d We examine the state changes of hESCs by overexpressing 714 transgenes individually d Nearly all genes, including heterochromatin genes, are perturbed by these transgenes d Transcription factors are grouped for hESC differentiation into specific lineages

Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive.Here we have identified meiosis-specific kinetochore factor MEIKIN in mouse, which functions in meiosis I but neither in meiosis II nor in mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated largely by the activity of Polo-like kinase PLK1, which is enriched to kinetochores depending on MEIKIN. Our integrative analysis indicates that MEIKIN is the long awaited key regulator of meiotic kinetochore function, which is conserved from yeasts to humans. 2In mitosis, sister chromatid cohesion is established depending on cohesin in S phase and maintained until metaphase when the sister chromatids are captured by spindle microtubules from opposite poles and aligned on the spindle equator. For the onset of anaphase, the anaphase-promoting complex (APC) triggers the degradation of securin, an inhibitory chaperone for separase that cleaves cohesin RAD21 and removes cohesin along the entire chromosome. This removal of cohesin triggers the separation of sister chromatids and their movement to opposite poles, a process called equational division [1][2][3] . During meiosis, however, meiotic cohesin REC8 largely replaces RAD21 along the entire chromosomes; one round of DNA replication is followed by two rounds of nuclear division, which results in four haploid nuclei or gametes (Fig. 1a).In the first division of meiosis (meiosis I), homologous chromosomes connected by chiasmata are captured from the opposite poles, while sisters are captured from the same pole (mono-orientation). At the onset of anaphase I, REC8 cohesin is cleaved by separase along the arm regions, but protected at centromeres until metaphase II 4-6 . Thus, mono-orientation and centromeric cohesion protection are two hallmarks of meiotic kinetochore function, which are widely conserved among eukaryotic organisms 7-9 (Fig. 1a). There is accumulating evidence that cohesion protection is mediated by the centromeric protein shugoshin (SGO) and its partner protein phosphatase 2A (PP2A) [10][11][12][13][14][15] , which antagonizes REC8 phosphorylation, a prerequisite of cleavage 16, 17 . So far, meiosis-specific kinetochore proteins have been identified only in two yeasts (S. cerevisiae Spo13 and Mam1 (monopolin subunit), and S. pombe Moa1) [18][19][20][21][22][23] . Puzzlingly, however, because their structural and functional similarities remain to be identified, conservation of meiotic kinetochore regulation is questionable even between yeasts 8, 9 . Therefore, in this study, we address the long-standing question of whether meiotic kinetochore regulation is conserved from yeasts to mammals, and, if so, how. Mammalian meiotic kinetochore protein MEIKINFission yeast Moa1 interacts directly with the conserved kinetochore protein Cnp3 (CENP-C homolog), and localizes to the kinetochore in meiosis I 24 . To identify an equivalent meiosis...