Epigenetic mechanisms play critical roles in establishment and maintenance of cell fate identity. Consistently, exome-sequencing studies have revealed that mutations in genes encoding epigenetic modifiers are significantly associated with neurodevelopmental disorders (NDDs) (doi.org/10.1038/nature13772). In particular, pathogenic mutations in genes encoding “writers” and “readers” of di- and trimethylation of histone H3 at lysine 9 (H3K9me2/3) are strongly linked to NDDs (doi.org/10.1016/j.nlm.2015.06.013/ doi.org/10.1038/nm.2828). Deposition of these histone modifications is traditionally associated with repetitive DNA sequences such as transposable elements (TEs) at constitutive heterochromatin. Recent evidence, however, indicates that H3K9-specific HTMases also play fundamental roles in stabilizing cell fate by silencing lineage non-specific genes during development (doi.org/10.1126/science.aau0583/ doi.org/10.1016/j.tig.2015.11.001). Indeed, the major euchromatic histone methyltransferases (HMTases) G9A and GLP, specific for H3K9me2, are essential for embryonic development and critical for repression of key developmental enhancers to enforce lineage-specific gene expression patterns (doi.org/10.1101/gad.989402/ doi.org/10.7554/eLife.09571). The ubiquitously expressed G9A and GLP enzymes lack intrinsic sequence-specificity. Therefore, major open questions in the field are: (1) how the precise targeting of heterochromatin to gene regulatory sequences is controlled, and (2) how disruption of these pathways is mechanistically link to genetic disorders. To identify regulators of G9A/GLP-dependent epigenetic gene silencing, we performed a CRISPR-Cas9 mediated mutagenesis screen in mouse embryonic stem cells (doi.org/10.1038/s41556-022-01051-2). This unexpectedly uncovered Zinc finger protein 462(Zfp462), an uncharacterized transcription factor, to be responsible for sequence-specific targeting of heterochromatin. Notably, its human ortholog, ZNF462, has recently been identified as a high-confidence NDD risk gene (doi.org/10.1038/ejhg.2017.86). Individuals with heterozygous mutations in ZNF462 present recurring phenotypes of multiple congenital anomalies, known as Weiss-Kruszka Syndrome (https://www.omim.org/entry/618619). Here, we find that heterozygous and homozygous Zfp462 mutations result in aberrant endodermal gene activation, which triggers spontaneous ESC differentiation and impairs lineage specification during neuronal differentiation. By further molecular characterization, we discovered that the murine homolog Zfp462 is involved in heritable transcriptional silencing at DNA binding sites that are critical for ESC- and endoderm-specific gene expression by recruiting H3K9-specific HMTase G9A/GLP and Heterochromatin Protein 1 (HP1). Our data strongly suggest that interference in neuronal lineage-specification by aberrant activation of endodermal genes at early steps of embryogenesis underlies the neurodevelopmental pathology associated with ZNF462 haploinsufficiency. Moreover, our findings uncover the molecular mechanism of cell lineage specification through G9A/GLP-dependent epigenetic silencing of unwanted gene regulatory networks, a prerequisite for embryogenesis.