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Oncogenic histone lysine-to-methionine mutations block the methylation of their corresponding lysine residues on wild-type histones. One attractive model is that these mutations sequester histone methyltransferases, but genome-wide studies show that mutant histones and histone methyltransferases often do not colocalize. Using chromatin immunoprecipitation sequencing (ChIP-seq), here, we show that, in fission yeast, even though H3K9M-containing nucleosomes are broadly distributed across the genome, the histone H3K9 methyltransferase Clr4 is mainly sequestered at pericentric repeats. This selective sequestration of Clr4 depends not only on H3K9M but also on H3K14 ubiquitylation (H3K14ub), a modification deposited by a Clr4-associated E3 ubiquitin ligase complex. In vitro, H3K14ub synergizes with H3K9M to interact with Clr4 and potentiates the inhibitory effects of H3K9M on Clr4 enzymatic activity. Moreover, binding kinetics show that H3K14ub overcomes the Clr4 aversion to H3K9M and reduces its dissociation. The selective sequestration model reconciles previous discrepancies and demonstrates the importance of protein-interaction kinetics in regulating biological processes.

Oncogenic histone lysine-to-methionine mutations block the methylation of their corresponding lysine residues on wild-type histones. One attractive model is that these mutations sequester histone methyltransferases, but genome-wide studies show that mutant histones and histone methyltransferases often do not colocalize. Using chromatin immunoprecipitation sequencing (ChIP-seq), here, we show that, in fission yeast, even though H3K9M-containing nucleosomes are broadly distributed across the genome, the histone H3K9 methyltransferase Clr4 is mainly sequestered at pericentric repeats. This selective sequestration of Clr4 depends not only on H3K9M but also on H3K14 ubiquitylation (H3K14ub), a modification deposited by a Clr4-associated E3 ubiquitin ligase complex. In vitro, H3K14ub synergizes with H3K9M to interact with Clr4 and potentiates the inhibitory effects of H3K9M on Clr4 enzymatic activity. Moreover, binding kinetics show that H3K14ub overcomes the Clr4 aversion to H3K9M and reduces its dissociation. The selective sequestration model reconciles previous discrepancies and demonstrates the importance of protein-interaction kinetics in regulating biological processes.

Childhood and adolescent overweight and obesity have been a global health concern in recent years with many negative implications for children's health and development. Previous research has suggested that as compared to normal weight children, children who are overweight or obese perform worse academically (Falkner et al., 2001), have more emotional problems (Storch et al., 2007; Zavodny, 2013), and encounter more problems in their interpersonal relationships with peers (Gable et al., 2012). These findings, however, are not always consistent. Three major limitations in the literature can be identified. First, many studies of the associations between children's and adolescents' weight or BMI and developmental outcomes have relied on BMI from a single-time point without considering the trajectory of children's and adolescents' weight development. To study the cumulative effects of overweight and obesity, it is important to examine children's and adolescents' weight patterns and to address questions such as whether children and adolescents who are consistently overweight are at higher risk for negative outcomes than are children and adolescents who become overweight over time. Second, most studies did not have nationally representative samples that would allow for an examination of ethnic differences. Third, no study has examined the protective (moderating) role of parenting when investigating the influence of children's and adolescents' weight trajectories on developmental outcomes. To overcome the above limitations of previous research, I used data from a nationally representative subsample of children in the Early Childhood Longitudinal Study, Kindergarten 1998-99 cohort (ECLS-K). First, I identified adolescents' different BMI trajectories across kindergarten to eighth grade by using Nagin & Land's (1993, 2012) group-based trajectory modeling (GBTM). Second, because previous research had shown ethnic and gender differences in the rates of childhood overweight a

Childhood and adolescent overweight and obesity have been a global health concern in recent years with many negative implications for children's health and development. Previous research has suggested that as compared to normal weight children, children who are overweight or obese perform worse academically (Falkner et al., 2001), have more emotional problems (Storch et al., 2007; Zavodny, 2013), and encounter more problems in their interpersonal relationships with peers (Gable et al., 2012). These findings, however, are not always consistent. Three major limitations in the literature can be identified. First, many studies of the associations between children's and adolescents' weight or BMI and developmental outcomes have relied on BMI from a single-time point without considering the trajectory of children's and adolescents' weight development. To study the cumulative effects of overweight and obesity, it is important to examine children's and adolescents' weight patterns and to address questions such as whether children and adolescents who are consistently overweight are at higher risk for negative outcomes than are children and adolescents who become overweight over time. Second, most studies did not have nationally representative samples that would allow for an examination of ethnic differences. Third, no study has examined the protective (moderating) role of parenting when investigating the influence of children's and adolescents' weight trajectories on developmental outcomes. To overcome the above limitations of previous research, I used data from a nationally representative subsample of children in the Early Childhood Longitudinal Study, Kindergarten 1998-99 cohort (ECLS-K). First, I identified adolescents' different BMI trajectories across kindergarten to eighth grade by using Nagin & Land's (1993, 2012) group-based trajectory modeling (GBTM). Second, because previous research had shown ethnic and gender differences in the rates of childhood overweight a